Advanced or Metastatic Solid Tumors
Conditions
Keywords
Drug Therapy
Brief summary
TAK-981 is being tested in combination with pembrolizumab to treat participants who have select advanced or metastatic solid tumors. The study aims are to evaluate the safety, tolerability, and preliminary efficacy of TAK-981 in combination with pembrolizumab. Participants will be on this combination treatment for 21-day cycles. They will continue with this treatment for up to 24 months or until participants meet any discontinuation criteria.
Detailed description
The drug being tested in this study is called TAK-981. TAK-981 is being tested to treat people who have select advanced or metastatic solid tumors. The study will include a dose escalation phase and a dose expansion phase. The study will enroll approximately 231 participants, approximately 32 participants in the dose escalation phase 1 and approximately 76 to 199 participants in the 8 cohorts of dose expansion phase 2. Participants will receive escalating doses of TAK-981 and fixed dose of pembrolizumab until recommended phase 2 dose (RP2D) is determined: • Dose Escalation: TAK-981 + Pembrolizumab (Fixed Dose) Once Phase 2 doses are identified, participants of select advanced or metastatic solid tumors will receive TAK-981 in below defined cohorts in the expansion phase 2: * Dose Expansion Phase: Cohort A: Non-squamous Non-small Cell Lung Cancer (NSCLC) * Dose Expansion Phase: Cohort B: Cervical Cancer * Dose Expansion Phase: Cohort C: Microsatellite Stable Colorectal Cancer (MSS-CRC) * Dose Expansion Phase: Cohort D: Cutaneous Melanoma * Dose Expansion Phase: Cohort E: Squamous NSCLC * Dose Expansion Phase: Cohort F: Checkpoint Inhibitors (CPI) Refractory Squamous or Nonsquamous NSCLC This multi-center trial will be conducted worldwide. The overall time to participate in this study is 60 months. Participants will make multiple visits to the clinic, and progression-free survival follow-up for maximum up to 12 months after last dose of study drug.
Interventions
DRUGTAK-981
TAK-981 IV infusion.
DRUGPembrolizumab
Pembrolizumab IV infusion.
Sponsors
Takeda Development Center Americas, Inc.
Takeda
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study has 2 Phases. Phase 1 is dose escalation phase with sequential drug assignment. Phase 2 is parallel assignment.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Has a histologically or cytologically documented, advanced (metastatic and/or unresectable) cancer as listed below that is incurable: Note: Prior neoadjuvant or adjuvant therapy included in initial treatment may not be considered first- or later-line standard of care treatment unless such treatments were completed less than 12 months prior to the current tumor recurrence. A. Non-squamous NSCLC for which prior standard first-line treatment containing an anti-programmed cell death protein 1/programmed cell death protein 1 ligand (PD-1/PD-L1) checkpoint inhibitor (CPI) alone or in combination has failed and that has progressed on no more than 1 prior systemic therapy. In Phase 2, participants with nonsquamous NSCLC must have not received more than 1 prior systemic therapy and must not have presented with disease progression during the first 6 months of treatment with first-line CPI/anti-PD-(1/L1)-containing therapy. Note: In Phase 1, participants with nonsquamous NSCLC and known driver mutations/genomic aberrations (e.g., epidermal growth factor receptor (EGFR), B-Raf proto-oncogene mutation V600E \[BRAF V600E\], and ROS proto-oncogene 1 \[ROS1\] sensitizing mutations, neurotrophic receptor tyrosine kinase \[NRTK\] gene fusions, and anaplastic lymphoma kinase \[ALK\] rearrangements) must have also shown progressive disease after treatment with a commercially available targeted therapy. In Phase 2, participants with driver mutations are not eligible. B. CPI-naive cervical cancer (squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma of the cervix) participants for whom prior standard first-line treatment has failed and who have received no more than 1 prior systemic line of therapy for recurrent or Stage IVB cervical cancer. Note: The following cervical tumors are not eligible: minimal deviation/adenoma malignum, gastric-type adenocarcinoma, clear-cell carcinoma, and mesonephric carcinoma. Histologic confirmation of the original primary tumor is required via pathology report. Note: First-line treatment must have consisted of platinum-containing doublet. Chemotherapy administered concurrently with primary radiation (e.g., weekly cisplatin) is not counted as a systemic chemotherapy regimen. C. CPI-naïve microsatellite stable-colorectal cancer (MSS-CRC) participants for whom prior standard first-line treatment has failed and who have progressed on no more than 3 chemotherapy regimens. Note: Participants must have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens if indicated. D. Unresectable Stage III or Stage IV cutaneous melanoma that has not received prior therapy in the metastatic setting. Note: Participants with acral melanoma are not eligible. Participants who have presented with disease relapse after ≥6 months of the last dose of CPI or BRAF-mitogen-activated protein kinase kinase (MEK) inhibitor in the adjuvant setting are eligible. E. Squamous NSCLC for which prior standard first-line treatment containing an anti-PD-(1/L1) checkpoint inhibitor alone or in combination has failed. Participant must have not received more than 1 prior systemic therapy and must not have presented with disease progression during the first 6 months of treatment with first-line CPI/anti-PD-(1/L1)-containing therapy. F. Squamous or nonsquamous NSCLC for which prior standard first-line treatment containing an anti-PD-(1/L1) checkpoint inhibitor alone or in combination has failed within 6 months from the initiation of the CPI. Participants must not have received more than 1 prior systemic therapy in the metastatic setting. Note: Participants with driver mutations are not eligible. 2. Has at least 1 radiologically measurable lesion based on RECIST, Version 1.1. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. 3. Has a performance status of 0 or 1 on the Eastern Cooperative Group Oncology (ECOG) Performance Scale. 4. Has left ventricular ejection fraction (LVEF) ≥40%; as measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan. 5. Has recovered to Grade 1 or baseline from all toxicity associated with previous therapy or have the toxicity established as sequela. Note: Has a neuropathy ≤Grade 2, any grade alopecia, or autoimmune endocrinopathies with stable replacement therapy are permitted. 6. Demonstrate adequate organ function as described below: A. Platelet count ≥75.0 × 10\^9/L. B. Absolute neutrophil count (ANC) ≥1.0 × 10\^9/L. C. Hemoglobin ≥85 g/L (red blood cell \[RBC\] transfusion allowed ≥14 days before assessment). D. Calculated creatinine clearance ≥30 mL/min using the Cockcroft-Gault formula. E. Aspartate aminotransferase (AST, GOT) and alanine aminotransferase (ALT, GPT) ≤3.0 times the upper limit of normal (ULN), \<5.0 times the ULN if liver enzyme elevations are due to liver metastases; bilirubin ≤1.5 times the ULN. Participants with Gilbert's syndrome may have a bilirubin level \>1.5 times the ULN, per discussion between the investigator and the medical monitor.
Exclusion criteria
1. History of uncontrolled brain metastasis (evidence of progression by imaging over a period of 4 weeks and/or neurologic symptoms that have not returned to baseline). Participant with treated brain metastases are allowed provided they are radiologically stable, without evidence of progression for at least 4 weeks by repeat imaging, clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment. Note: For asymptomatic participants, screening brain imaging is not required. 2. Second malignancy within the previous 3 years, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ, resected colorectal adenomatous polyps, breast cancer in situ, or other malignancy for which the participant is not on active anticancer therapy. 3. Major surgery ≤14 days from the first dose of study drug and not recovered fully from any complications from surgery. 4. History of immune-related AEs related to treatment with immune CPIs that required treatment discontinuation. 5. Receiving or requires the continued use of medications that are known to be strong or moderate inhibitors and inducers of cytochrome P-450 (CYP) 3A4/5 and strong P-glycoprotein (Pgp) inhibitors. 6. Baseline prolongation of the QT interval corrected using Fridericia's formula (QTcF) (e.g., repeated demonstration of QTcF interval \>480 milliseconds (ms), history of congenital long QT syndrome, or torsades de pointes). 7. Has a history of autoimmune disease requiring systemic immunosuppressive therapy with daily doses of prednisone \>10 mg/day or equivalent doses, or any other form of immunosuppressive therapy. Hormone replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for thyroid, adrenal or pituitary insufficiency) for endocrinopathies are not considered prohibited forms of systemic treatment of an autoimmune disease. 8. Has a history of noninfectious pneumonitis that required steroids or a history of interstitial lung disease. 9. Has an evidence of active, non-infectious pneumonitis. 10. Has a history of allogeneic tissue or solid organ transplant. 11. Has an active infection requiring systemic therapy. 12. Has a known history of human immunodeficiency virus (HIV) infection or any other relevant congenital or acquired immunodeficiency. 13. Has a known hepatitis B virus surface antigen seropositive or detectable hepatitis C infection viral load. Note: Participants who have positive hepatitis B core antibody or hepatitis B surface antigen antibody can be enrolled but must have an undetectable hepatitis B viral load. 14. History of any of the following ≤6 months before first dose: congestive heart failure New York Heart Association Grade III or IV, unstable angina, myocardial infarction, unstable symptomatic ischemic heart disease, uncontrolled hypertension despite appropriate medical therapy, ongoing symptomatic cardiac arrhythmias \>Grade 2, pulmonary embolism or symptomatic cerebrovascular events, or any other serious cardiac condition (e.g., pericardial effusion or restrictive cardiomyopathy). Chronic atrial fibrillation on stable anticoagulant therapy is allowed. 15. Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of AEs or has compromised ability to provide written informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs) | Up to approximately 24 months | An adverse event (AE) is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy. AEs were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0 except cytokine release syndrome (CRS), which was graded according to American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading for CRS. |
| Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | Up to Cycle 1 (each cycle was of 21 days) | DLTs were evaluated according to NCI CTCAE Version 5.0 except CRS, which was graded according to ASTCT Consensus Grading for CRS. |
| Phase 1: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) | Up to approximately 24 months | AE means any untoward medical occurrence in a participant administered a pharmaceutical product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product whether or not it is related to the medicinal product. A TEAE was defined as an adverse event which occurred on or after the first dose of study drug and no more than 30 days after the last dose of study drug. A severity grade was evaluated as per the NCI CTCAE Version 5.0, except for CRS, which was assessed by ASTCT Consensus Grading for CRS. |
| Phase 1: Number of Participants With One or More Serious Adverse Events (SAEs) | Up to approximately 24 months | An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. |
| Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | Up to approximately 24 months | An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy. |
| Phase 1: Number of Participants With Clinically Significant Laboratory Values | Up to approximately 24 months | Laboratory parameters included clinical chemistry, hematology, and urinalysis. Participants with at least 1 Grade 3 or 4 Lab Abnormalities were reported. |
| Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1 | Up to approximately 25 months | ORR is defined as the percentage of participants who achieve Complete Response (CR) and Partial Response (PR) (determined by the investigator) during the study according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phases 1 and 2: Disease Control Rate (DCR) | Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months | DCR is defined as the percentage of participants who achieved stable disease (SD) or better (CR + PR + SD determined by the investigator) \>6 weeks during the trial in the response-evaluable population. |
| Phases 1 and 2: Durable Response Rate (DRR) | Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months | DRR is defined as the rate of objective responses (CR + PR) maintained for at least 6 months initiating at any time within 12 months of commencing therapy. |
| Phases 1 and 2: Duration of Response (DOR) | Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months | DOR is defined as a time from the time of first documentation of tumor response to the first recorded occurrence of disease progression (PD) or death from any cause (whichever occurs first), through end of study. |
| Phases 1 and 2: Progression-free Survival (PFS) | Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months | PFS is defined as time from the date of the first dose administration to the date of first documentation of PD or death due to any cause whichever occurs first, through the end of the study. |
| Phases 1 and 2: Time to Response (TTR) | Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months | TTR is defined as time from the date of the first dose administration to the date of first documented PR or better. |
| Phases 1 and 2: Time to Progression (TTP) | Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months | TTP is defined as the from the date of the first dose administration to the date of the first documentation of PD as defined by standard disease criteria. |
| Phase 1: Cmax: Maximum Observed Plasma Concentration for TAK-981 | Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) | — |
| Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 1 (1 hour, 4 hours, 8 hours) and Day 8 (Pre-dose, 1 hour, 4 hours and 8 hours) (Cycle length = 21 days) | The level of TAK-981-SUMO adduct formation was evaluated by flow cytometry as the percentage of adduct formed in peripheral blood lymphocytes. Fold change from baseline was calculated as: Post-treatment value / Baseline value. Positive change denotes improvement. |
| Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 1 (1 hour, 4 hours, 8 hours) and Day 8 (Pre-dose, 1 hour, 4 hours and 8 hours) (Cycle length = 21 days) | SUMO pathway inhibition in blood was evaluated by flow cytometry in peripheral blood lymphocytes with an antibody recognizing SUMO 2/3 chains. Fold change from baseline was calculated as: Post-treatment value / Baseline value. |
| Phase 2: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs) | Up to approximately 25 months | An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy. AEs were evaluated according to NCI CTCAE, Version 5.0 except CRS, which was graded according to ASTCT Consensus Grading for CRS. |
| Phase 2: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) | Up to approximately 25 months | An AE means any untoward medical occurrence in a participant administered a pharmaceutical product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product whether or not it is related to the medicinal product. A TEAE was defined as an adverse event which occurred on or after the first dose of study drug and no more than 30 days after the last dose of study drug. A severity grade was evaluated as per the NCI CTCAE Version 5.0, except for CRS, which was assessed by ASTCT Consensus Grading for CRS. |
| Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | Up to approximately 25 months | An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy. |
| Phase 2: Overall Survival (OS) | Up to approximately 25 months | OS is defined as the time from the date of the first dose administration to the date of death. Participants without documentation of death at the time of analysis were censored at the date last known to be alive. |
| Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981 | Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) | — |
| Phase 1: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-981 | Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) | — |
| Phase 1: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981 | Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) | — |
| Phase 1: t1/2z: Terminal Disposition Phase Half-life for TAK-981 | Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) | — |
| Phase 1: CL: Total Clearance After Intravenous Administration for TAK-981 | Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) | — |
| Phase 1: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981 | Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) | — |
Countries
Brazil, China, Croatia, Japan, Latvia, Lithuania, Poland, Switzerland, United States
Participant flow
Recruitment details
Participants took part in the study at various investigative sites throughout the world from 17 August 2020 to 29 October 2024.
Pre-assignment details
Participants with a diagnosis of advanced or metastatic solid tumors were enrolled in this study consisting of Phase 1b (Dose Escalation cohorts), and Phase 2 (Dose Expansion cohorts) periods to receive TAK-981 and pembrolizumab.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation: TAK-981 40 mg Participants received TAK-981 40 mg, IV infusion, on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle and pembrolizumab 200 mg, IV infusion, as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle until the RP2D was determined (for a maximum of 24 months). | 3 |
| Dose Escalation: TAK-981 60 mg Participants received TAK-981 60 mg, IV infusion, on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle and pembrolizumab 200 mg, IV infusion, as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle until the RP2D was determined (for a maximum of 24 months). | 6 |
| Dose Escalation: TAK-981 90 mg Participants received TAK-981 90 mg, IV infusion, on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle and pembrolizumab 200 mg, IV infusion, as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle until the RP2D was determined (for a maximum of 24 months). | 33 |
| Dose Escalation: TAK-981 120 mg Participants received TAK-981 120 mg, IV infusion, on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle and pembrolizumab 200 mg, IV infusion, as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle until the RP2D was determined (for a maximum of 24 months). | 19 |
| Dose Expansion: Cohort A: Non-squamous NSCLC TAK-981 90 mg Participants with non-squamous NSCLC received TAK-981 90 mg as IV infusion on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months. | 14 |
| Dose Expansion: Cohort A: Non-squamous NSCLC TAK-981 120 mg Participants with non-squamous NSCLC received TAK-981 120 mg as IV infusion on Days 1 and 8 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months. | 9 |
| Dose Expansion: Cohort B: Cervical Cancer TAK-981 90 mg Participants with cervical cancer received TAK-981 90 mg as IV infusion on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months. | 21 |
| Dose Expansion: Cohort C: MSS-CRC TAK-981 90 mg Participants with MSS-CRC received TAK-981 90 mg as IV infusion on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months. | 9 |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg Participants with cutaneous melanoma received TAK-981 90 mg as IV infusion on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months. | 28 |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg Participants with squamous NSCLC received TAK-981 90 mg as IV infusion on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months. | 15 |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg Participants with CPI refractory squamous and non-squamous NSCLC received TAK-981 90 mg as IV infusion on Days 1, 4, 8 and 11 or Days 1 and 8 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months. | 4 |
| Total | 161 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1b (Dose Escalation) | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1b (Dose Escalation) | New anti-cancer therapy | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1b (Dose Escalation) | Progressive Disease | 1 | 3 | 12 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1b (Dose Escalation) | Reason Not Specified | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1b (Dose Escalation) | Withdrawal by Subject | 0 | 0 | 11 | 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 2 (Dose Expansion) | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 0 |
| Phase 2 (Dose Expansion) | New anti-cancer therapy | 0 | 0 | 0 | 0 | 3 | 1 | 0 | 0 | 0 | 2 | 0 |
| Phase 2 (Dose Expansion) | Progressive Disease | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 3 | 3 | 4 | 2 |
| Phase 2 (Dose Expansion) | Reason Not Specified | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Phase 2 (Dose Expansion) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 2 | 4 | 2 | 1 | 4 | 1 |
Baseline characteristics
| Characteristic | Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Total | Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Dose Escalation: TAK-981 40 mg | Dose Escalation: TAK-981 60 mg | Dose Escalation: TAK-981 90 mg | Dose Escalation: TAK-981 120 mg | Dose Expansion: Cohort A: Non-squamous NSCLC TAK-981 90 mg | Dose Expansion: Cohort A: Non-squamous NSCLC TAK-981 120 mg | Dose Expansion: Cohort B: Cervical Cancer TAK-981 90 mg | Dose Expansion: Cohort C: MSS-CRC TAK-981 90 mg | Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 67.5 years STANDARD_DEVIATION 7.66 | 58.5 years STANDARD_DEVIATION 12.82 | 73.5 years STANDARD_DEVIATION 3.7 | 66.0 years STANDARD_DEVIATION 5.57 | 53.5 years STANDARD_DEVIATION 7.23 | 56.2 years STANDARD_DEVIATION 11.91 | 59.8 years STANDARD_DEVIATION 13.32 | 63.3 years STANDARD_DEVIATION 10.83 | 68.7 years STANDARD_DEVIATION 9.12 | 51.8 years STANDARD_DEVIATION 13.24 | 49.6 years STANDARD_DEVIATION 9.22 | 55.9 years STANDARD_DEVIATION 13.95 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 41 Participants | 0 Participants | 2 Participants | 1 Participants | 6 Participants | 1 Participants | 5 Participants | 0 Participants | 12 Participants | 0 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 116 Participants | 4 Participants | 1 Participants | 5 Participants | 25 Participants | 18 Participants | 8 Participants | 9 Participants | 9 Participants | 9 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 35 Participants | 0 Participants | 0 Participants | 4 Participants | 8 Participants | 7 Participants | 3 Participants | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 8 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 10 Participants | 110 Participants | 4 Participants | 3 Participants | 2 Participants | 17 Participants | 9 Participants | 10 Participants | 8 Participants | 17 Participants | 7 Participants | 23 Participants |
| Sex: Female, Male Female | 1 Participants | 81 Participants | 1 Participants | 1 Participants | 5 Participants | 16 Participants | 8 Participants | 6 Participants | 5 Participants | 21 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Male | 14 Participants | 80 Participants | 3 Participants | 2 Participants | 1 Participants | 17 Participants | 11 Participants | 8 Participants | 4 Participants | 0 Participants | 4 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 2 / 6 | 8 / 33 | 4 / 19 | 2 / 14 | 4 / 9 | 9 / 21 | 2 / 9 | 8 / 28 | 2 / 15 | 1 / 4 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 33 / 33 | 19 / 19 | 14 / 14 | 9 / 9 | 21 / 21 | 9 / 9 | 28 / 28 | 14 / 15 | 4 / 4 |
| serious Total, serious adverse events | 0 / 3 | 3 / 6 | 17 / 33 | 10 / 19 | 3 / 14 | 4 / 9 | 11 / 21 | 4 / 9 | 14 / 28 | 5 / 15 | 3 / 4 |
Outcome results
Primary
Phase 1: Number of Participants With Clinically Significant Laboratory Values
Laboratory parameters included clinical chemistry, hematology, and urinalysis. Participants with at least 1 Grade 3 or 4 Lab Abnormalities were reported.
Time frame: Up to approximately 24 months
Population: Safety Analysis Set included participants who received at least 1 dose, even if incomplete, of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Hematology | 1 Participants |
| Dose Escalation: TAK-981 40 mg | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Coagulation | 0 Participants |
| Dose Escalation: TAK-981 40 mg | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Serum Chemistry | 1 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Hematology | 3 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Coagulation | 0 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Serum Chemistry | 1 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Serum Chemistry | 7 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Hematology | 7 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Coagulation | 0 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Hematology | 6 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Coagulation | 1 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 1: Number of Participants With Clinically Significant Laboratory Values | Serum Chemistry | 5 Participants |
Primary
Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
DLTs were evaluated according to NCI CTCAE Version 5.0 except CRS, which was graded according to ASTCT Consensus Grading for CRS.
Time frame: Up to Cycle 1 (each cycle was of 21 days)
Population: The DLT-evaluable Analysis Set included participants enrolled in Phase 1b of the study and who experienced a DLT at any time after receiving the first dose of TAK-981 during the DLT assessment period (Cycle 1) or who received all planned TAK-981 doses and 1 administration of pembrolizumab in Cycle 1.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
Primary
Phase 1: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs)
AE means any untoward medical occurrence in a participant administered a pharmaceutical product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product whether or not it is related to the medicinal product. A TEAE was defined as an adverse event which occurred on or after the first dose of study drug and no more than 30 days after the last dose of study drug. A severity grade was evaluated as per the NCI CTCAE Version 5.0, except for CRS, which was assessed by ASTCT Consensus Grading for CRS.
Time frame: Up to approximately 24 months
Population: Safety Analysis Set included participants who received at least 1 dose, even if incomplete, of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 1: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) | 0 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 1: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) | 2 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 1: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) | 20 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 1: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) | 15 Participants |
Primary
Phase 1: Number of Participants With One or More Serious Adverse Events (SAEs)
An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent.
Time frame: Up to approximately 24 months
Population: Safety Analysis Set included participants who received at least 1 dose, even if incomplete, of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 1: Number of Participants With One or More Serious Adverse Events (SAEs) | 0 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 1: Number of Participants With One or More Serious Adverse Events (SAEs) | 3 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 1: Number of Participants With One or More Serious Adverse Events (SAEs) | 17 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 1: Number of Participants With One or More Serious Adverse Events (SAEs) | 10 Participants |
Primary
Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation
An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.
Time frame: Up to approximately 24 months
Population: Safety Analysis Set included participants who received at least 1 dose, even if incomplete, of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of TAK-981 | 0 Participants |
| Dose Escalation: TAK-981 40 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of Pembrolizumab | 0 Participants |
| Dose Escalation: TAK-981 40 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of TAK-981 | 0 Participants |
| Dose Escalation: TAK-981 40 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of Pembrolizumab | 0 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of Pembrolizumab | 3 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of TAK-981 | 1 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of Pembrolizumab | 1 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of TAK-981 | 3 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of TAK-981 | 3 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of Pembrolizumab | 15 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of Pembrolizumab | 4 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of TAK-981 | 22 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of Pembrolizumab | 1 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of Pembrolizumab | 4 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of TAK-981 | 11 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 1: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of TAK-981 | 2 Participants |
Primary
Phase 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs)
An adverse event (AE) is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy. AEs were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0 except cytokine release syndrome (CRS), which was graded according to American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading for CRS.
Time frame: Up to approximately 24 months
Population: Safety Analysis Set included participants who received at least 1 dose, even if incomplete, of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs) | 6 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs) | 33 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs) | 19 Participants |
Primary
Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1
ORR is defined as the percentage of participants who achieve Complete Response (CR) and Partial Response (PR) (determined by the investigator) during the study according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
Time frame: Up to approximately 25 months
Population: Response-Evaluable Analysis Set included participants who had received at least 1 dose of study drug, had sites of measurable disease at baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happened.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1 | 20 percentage of participants |
| Dose Escalation: TAK-981 60 mg | Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1 | 0 percentage of participants |
| Dose Escalation: TAK-981 90 mg | Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1 | 30 percentage of participants |
| Dose Escalation: TAK-981 120 mg | Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1 | 0 percentage of participants |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1 | 25 percentage of participants |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1 | 7.7 percentage of participants |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1 | 0 percentage of participants |
Secondary
Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes
SUMO pathway inhibition in blood was evaluated by flow cytometry in peripheral blood lymphocytes with an antibody recognizing SUMO 2/3 chains. Fold change from baseline was calculated as: Post-treatment value / Baseline value.
Time frame: Cycle 1 Day 1 (1 hour, 4 hours, 8 hours) and Day 8 (Pre-dose, 1 hour, 4 hours and 8 hours) (Cycle length = 21 days)
Population: Pharmacodynamic Analysis Set included participants who provided evaluable blood samples (Cycle 1, Day 1 predose sample and at least 1 postdose sample). Overall number of participants analyzed is the number of participants with data available for analysis. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: TAK-981 40 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 1 Hour Post Dose | 0.7 unitless ratio | Standard Deviation 0.14 |
| Dose Escalation: TAK-981 40 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 4 Hours Post Dose | 0.7 unitless ratio | Standard Deviation 0.22 |
| Dose Escalation: TAK-981 40 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 1 Hour Post Dose | 0.6 unitless ratio | Standard Deviation 0.14 |
| Dose Escalation: TAK-981 40 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 4 Hours Post Dose | 0.8 unitless ratio | Standard Deviation 0.07 |
| Dose Escalation: TAK-981 40 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 6-8 Hours Post Dose | 0.7 unitless ratio | Standard Deviation 0.29 |
| Dose Escalation: TAK-981 40 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 6-8 Hours Post Dose | 0.8 unitless ratio | Standard Deviation 0.08 |
| Dose Escalation: TAK-981 40 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: Predose | 0.9 unitless ratio | Standard Deviation 0.24 |
| Dose Escalation: TAK-981 60 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 4 Hours Post Dose | 0.6 unitless ratio | Standard Deviation 0.15 |
| Dose Escalation: TAK-981 60 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: Predose | 1.0 unitless ratio | Standard Deviation 0.35 |
| Dose Escalation: TAK-981 60 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 6-8 Hours Post Dose | 0.7 unitless ratio | Standard Deviation 0.19 |
| Dose Escalation: TAK-981 60 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 1 Hour Post Dose | 0.6 unitless ratio | Standard Deviation 0.23 |
| Dose Escalation: TAK-981 60 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 6-8 Hours Post Dose | 0.6 unitless ratio | Standard Deviation 0.11 |
| Dose Escalation: TAK-981 60 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 4 Hours Post Dose | 0.6 unitless ratio | Standard Deviation 0.12 |
| Dose Escalation: TAK-981 60 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 1 Hour Post Dose | 0.6 unitless ratio | Standard Deviation 0.21 |
| Dose Escalation: TAK-981 90 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: Predose | 0.9 unitless ratio | Standard Deviation 0.36 |
| Dose Escalation: TAK-981 90 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 1 Hour Post Dose | 0.6 unitless ratio | Standard Deviation 0.18 |
| Dose Escalation: TAK-981 90 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 4 Hours Post Dose | 0.9 unitless ratio | Standard Deviation 0.54 |
| Dose Escalation: TAK-981 90 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 6-8 Hours Post Dose | 1.0 unitless ratio | Standard Deviation 0.68 |
| Dose Escalation: TAK-981 90 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 1 Hour Post Dose | 0.7 unitless ratio | Standard Deviation 0.34 |
| Dose Escalation: TAK-981 90 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 4 Hours Post Dose | 0.8 unitless ratio | Standard Deviation 0.58 |
| Dose Escalation: TAK-981 90 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 6-8 Hours Post Dose | 0.9 unitless ratio | Standard Deviation 0.53 |
| Dose Escalation: TAK-981 120 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 6-8 Hours Post Dose | 0.7 unitless ratio | Standard Deviation 0.34 |
| Dose Escalation: TAK-981 120 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 6-8 Hours Post Dose | 0.6 unitless ratio | Standard Deviation 0.22 |
| Dose Escalation: TAK-981 120 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 4 Hours Post Dose | 0.5 unitless ratio | Standard Deviation 0.17 |
| Dose Escalation: TAK-981 120 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 4 Hours Post Dose | 0.6 unitless ratio | Standard Deviation 0.11 |
| Dose Escalation: TAK-981 120 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 1 Hour Post Dose | 0.5 unitless ratio | Standard Deviation 0.08 |
| Dose Escalation: TAK-981 120 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 1 Hour Post Dose | 0.4 unitless ratio | Standard Deviation 0.15 |
| Dose Escalation: TAK-981 120 mg | Fold Change From Baseline in SUMO 2/3 Inhibition in Peripheral Blood Lymphocytes | Cycle 1 Day 8: Predose | 0.7 unitless ratio | Standard Deviation 0.39 |
Secondary
Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes
The level of TAK-981-SUMO adduct formation was evaluated by flow cytometry as the percentage of adduct formed in peripheral blood lymphocytes. Fold change from baseline was calculated as: Post-treatment value / Baseline value. Positive change denotes improvement.
Time frame: Cycle 1 Day 1 (1 hour, 4 hours, 8 hours) and Day 8 (Pre-dose, 1 hour, 4 hours and 8 hours) (Cycle length = 21 days)
Population: Pharmacodynamic Analysis Set included participants who provided evaluable blood samples (Cycle 1, Day 1 predose sample and at least 1 postdose sample). Overall number of participants analyzed is the number of participants with data available for analysis. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: TAK-981 40 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 1 Hour Post Dose | 8.1 unitless ratio | Standard Deviation 1.06 |
| Dose Escalation: TAK-981 40 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 4 Hours Post Dose | 7.5 unitless ratio | Standard Deviation 1.52 |
| Dose Escalation: TAK-981 40 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 1 Hour Post Dose | 11.9 unitless ratio | Standard Deviation 3.52 |
| Dose Escalation: TAK-981 40 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 4 Hours Post Dose | 5.1 unitless ratio | Standard Deviation 0.82 |
| Dose Escalation: TAK-981 40 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 6-8 Hours Post Dose | 6.5 unitless ratio | Standard Deviation 1.08 |
| Dose Escalation: TAK-981 40 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 6-8 Hours Post Dose | 4.6 unitless ratio | Standard Deviation 0.61 |
| Dose Escalation: TAK-981 40 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: Predose | 3.5 unitless ratio | Standard Deviation 0.53 |
| Dose Escalation: TAK-981 60 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 4 Hours Post Dose | 6.0 unitless ratio | Standard Deviation 2.66 |
| Dose Escalation: TAK-981 60 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: Predose | 2.6 unitless ratio | Standard Deviation 0.96 |
| Dose Escalation: TAK-981 60 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 6-8 Hours Post Dose | 4.5 unitless ratio | Standard Deviation 1.87 |
| Dose Escalation: TAK-981 60 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 1 Hour Post Dose | 7.7 unitless ratio | Standard Deviation 2.88 |
| Dose Escalation: TAK-981 60 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 6-8 Hours Post Dose | 5.1 unitless ratio | Standard Deviation 2.3 |
| Dose Escalation: TAK-981 60 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 4 Hours Post Dose | 5.0 unitless ratio | Standard Deviation 1.9 |
| Dose Escalation: TAK-981 60 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 1 Hour Post Dose | 7.0 unitless ratio | Standard Deviation 3.12 |
| Dose Escalation: TAK-981 90 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: Predose | 2.7 unitless ratio | Standard Deviation 1.43 |
| Dose Escalation: TAK-981 90 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 1 Hour Post Dose | 8.5 unitless ratio | Standard Deviation 3.38 |
| Dose Escalation: TAK-981 90 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 4 Hours Post Dose | 6.0 unitless ratio | Standard Deviation 1.8 |
| Dose Escalation: TAK-981 90 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 6-8 Hours Post Dose | 5.3 unitless ratio | Standard Deviation 1.58 |
| Dose Escalation: TAK-981 90 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 1 Hour Post Dose | 9.2 unitless ratio | Standard Deviation 4.68 |
| Dose Escalation: TAK-981 90 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 4 Hours Post Dose | 6.4 unitless ratio | Standard Deviation 2.9 |
| Dose Escalation: TAK-981 90 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 6-8 Hours Post Dose | 5.7 unitless ratio | Standard Deviation 2.64 |
| Dose Escalation: TAK-981 120 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 6-8 Hours Post Dose | 5.5 unitless ratio | Standard Deviation 1.29 |
| Dose Escalation: TAK-981 120 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 6-8 Hours Post Dose | 5.6 unitless ratio | Standard Deviation 1.96 |
| Dose Escalation: TAK-981 120 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 4 Hours Post Dose | 6.1 unitless ratio | Standard Deviation 2.12 |
| Dose Escalation: TAK-981 120 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 4 Hours Post Dose | 6.3 unitless ratio | Standard Deviation 1.7 |
| Dose Escalation: TAK-981 120 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 1: 1 Hour Post Dose | 8.4 unitless ratio | Standard Deviation 2.4 |
| Dose Escalation: TAK-981 120 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: 1 Hour Post Dose | 8.7 unitless ratio | Standard Deviation 2.01 |
| Dose Escalation: TAK-981 120 mg | Fold Change From Baseline in TAK-981-/Small Ubiquitin-like Modifier (SUMO) Adduct Formation in Peripheral Blood Lymphocytes | Cycle 1 Day 8: Predose | 2.0 unitless ratio | Standard Deviation 0.68 |
Secondary
Phase 1: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-981
Time frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Population: PK Analysis Set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Overall number of participants analyzed is the number of participants with data available for analysis. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 1: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-981 | Cycle 1 Day 1 | 880 hours*ng/mL | Standard Deviation 427 |
| Dose Escalation: TAK-981 40 mg | Phase 1: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-981 | Cycle 1 Day 8 | 814 hours*ng/mL | Standard Deviation 290 |
| Dose Escalation: TAK-981 60 mg | Phase 1: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-981 | Cycle 1 Day 8 | 976 hours*ng/mL | Standard Deviation 232 |
| Dose Escalation: TAK-981 60 mg | Phase 1: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-981 | Cycle 1 Day 1 | 1370 hours*ng/mL | Standard Deviation 517 |
| Dose Escalation: TAK-981 90 mg | Phase 1: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-981 | Cycle 1 Day 1 | 1950 hours*ng/mL | Standard Deviation 735 |
| Dose Escalation: TAK-981 90 mg | Phase 1: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-981 | Cycle 1 Day 8 | 1780 hours*ng/mL | Standard Deviation 908 |
| Dose Escalation: TAK-981 120 mg | Phase 1: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-981 | Cycle 1 Day 1 | 2580 hours*ng/mL | Standard Deviation 949 |
| Dose Escalation: TAK-981 120 mg | Phase 1: AUC0-t: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-981 | Cycle 1 Day 8 | 2640 hours*ng/mL | Standard Deviation 1260 |
Secondary
Phase 1: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981
Time frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Population: PK Analysis Set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Overall number of participants analyzed is the number of participants with data available for analysis. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 1: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981 | Cycle 1 Day 1 | 909 hours*ng/mL | Standard Deviation 432 |
| Dose Escalation: TAK-981 40 mg | Phase 1: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981 | Cycle 1 Day 8 | 845 hours*ng/mL | Standard Deviation 292 |
| Dose Escalation: TAK-981 60 mg | Phase 1: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981 | Cycle 1 Day 8 | 1010 hours*ng/mL | Standard Deviation 233 |
| Dose Escalation: TAK-981 60 mg | Phase 1: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981 | Cycle 1 Day 1 | 1400 hours*ng/mL | Standard Deviation 530 |
| Dose Escalation: TAK-981 90 mg | Phase 1: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981 | Cycle 1 Day 1 | 2020 hours*ng/mL | Standard Deviation 760 |
| Dose Escalation: TAK-981 90 mg | Phase 1: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981 | Cycle 1 Day 8 | 1830 hours*ng/mL | Standard Deviation 942 |
| Dose Escalation: TAK-981 120 mg | Phase 1: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981 | Cycle 1 Day 1 | 2660 hours*ng/mL | Standard Deviation 1020 |
| Dose Escalation: TAK-981 120 mg | Phase 1: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-981 | Cycle 1 Day 8 | 2750 hours*ng/mL | Standard Deviation 1320 |
Secondary
Phase 1: CL: Total Clearance After Intravenous Administration for TAK-981
Time frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Population: PK Analysis Set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Overall number of participants analyzed is the number of participants with data available for analysis. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 1: CL: Total Clearance After Intravenous Administration for TAK-981 | Cycle 1 Day 1 | 51.1 liters per hour (L/h) | Standard Deviation 23.2 |
| Dose Escalation: TAK-981 40 mg | Phase 1: CL: Total Clearance After Intravenous Administration for TAK-981 | Cycle 1 Day 8 | 51.7 liters per hour (L/h) | Standard Deviation 19.3 |
| Dose Escalation: TAK-981 60 mg | Phase 1: CL: Total Clearance After Intravenous Administration for TAK-981 | Cycle 1 Day 8 | 62.5 liters per hour (L/h) | Standard Deviation 15.5 |
| Dose Escalation: TAK-981 60 mg | Phase 1: CL: Total Clearance After Intravenous Administration for TAK-981 | Cycle 1 Day 1 | 47.2 liters per hour (L/h) | Standard Deviation 14.8 |
| Dose Escalation: TAK-981 90 mg | Phase 1: CL: Total Clearance After Intravenous Administration for TAK-981 | Cycle 1 Day 1 | 51.3 liters per hour (L/h) | Standard Deviation 19.6 |
| Dose Escalation: TAK-981 90 mg | Phase 1: CL: Total Clearance After Intravenous Administration for TAK-981 | Cycle 1 Day 8 | 57.0 liters per hour (L/h) | Standard Deviation 21.8 |
| Dose Escalation: TAK-981 120 mg | Phase 1: CL: Total Clearance After Intravenous Administration for TAK-981 | Cycle 1 Day 1 | 51.0 liters per hour (L/h) | Standard Deviation 18.4 |
| Dose Escalation: TAK-981 120 mg | Phase 1: CL: Total Clearance After Intravenous Administration for TAK-981 | Cycle 1 Day 8 | 53.8 liters per hour (L/h) | Standard Deviation 26.8 |
Secondary
Phase 1: Cmax: Maximum Observed Plasma Concentration for TAK-981
Time frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Population: Pharmacokinetic (PK) Analysis Set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for TAK-981 | Cycle 1 Day 1 | 335 nanograms per milliliter (ng/ml) | Standard Deviation 282 |
| Dose Escalation: TAK-981 40 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for TAK-981 | Cycle 1 Day 8 | 280 nanograms per milliliter (ng/ml) | Standard Deviation 167 |
| Dose Escalation: TAK-981 60 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for TAK-981 | Cycle 1 Day 8 | 448 nanograms per milliliter (ng/ml) | Standard Deviation 206 |
| Dose Escalation: TAK-981 60 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for TAK-981 | Cycle 1 Day 1 | 728 nanograms per milliliter (ng/ml) | Standard Deviation 396 |
| Dose Escalation: TAK-981 90 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for TAK-981 | Cycle 1 Day 8 | 780 nanograms per milliliter (ng/ml) | Standard Deviation 524 |
| Dose Escalation: TAK-981 90 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for TAK-981 | Cycle 1 Day 1 | 888 nanograms per milliliter (ng/ml) | Standard Deviation 423 |
| Dose Escalation: TAK-981 120 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for TAK-981 | Cycle 1 Day 8 | 1270 nanograms per milliliter (ng/ml) | Standard Deviation 770 |
| Dose Escalation: TAK-981 120 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for TAK-981 | Cycle 1 Day 1 | 1290 nanograms per milliliter (ng/ml) | Standard Deviation 571 |
Secondary
Phase 1: t1/2z: Terminal Disposition Phase Half-life for TAK-981
Time frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Population: PK Analysis Set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Overall number of participants analyzed is the number of participants with data available for analysis. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 1: t1/2z: Terminal Disposition Phase Half-life for TAK-981 | Cycle 1 Day 1 | 5.88 hours |
| Dose Escalation: TAK-981 40 mg | Phase 1: t1/2z: Terminal Disposition Phase Half-life for TAK-981 | Cycle 1 Day 8 | 5.83 hours |
| Dose Escalation: TAK-981 60 mg | Phase 1: t1/2z: Terminal Disposition Phase Half-life for TAK-981 | Cycle 1 Day 8 | 5.68 hours |
| Dose Escalation: TAK-981 60 mg | Phase 1: t1/2z: Terminal Disposition Phase Half-life for TAK-981 | Cycle 1 Day 1 | 5.58 hours |
| Dose Escalation: TAK-981 90 mg | Phase 1: t1/2z: Terminal Disposition Phase Half-life for TAK-981 | Cycle 1 Day 1 | 5.72 hours |
| Dose Escalation: TAK-981 90 mg | Phase 1: t1/2z: Terminal Disposition Phase Half-life for TAK-981 | Cycle 1 Day 8 | 6.06 hours |
| Dose Escalation: TAK-981 120 mg | Phase 1: t1/2z: Terminal Disposition Phase Half-life for TAK-981 | Cycle 1 Day 1 | 6.79 hours |
| Dose Escalation: TAK-981 120 mg | Phase 1: t1/2z: Terminal Disposition Phase Half-life for TAK-981 | Cycle 1 Day 8 | 6.67 hours |
Secondary
Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981
Time frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Population: PK Analysis Set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981 | Cycle 1 Day 1 | 1.22 hours |
| Dose Escalation: TAK-981 40 mg | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981 | Cycle 1 Day 8 | 1.18 hours |
| Dose Escalation: TAK-981 60 mg | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981 | Cycle 1 Day 8 | 1.41 hours |
| Dose Escalation: TAK-981 60 mg | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981 | Cycle 1 Day 1 | 1.27 hours |
| Dose Escalation: TAK-981 90 mg | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981 | Cycle 1 Day 1 | 1.17 hours |
| Dose Escalation: TAK-981 90 mg | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981 | Cycle 1 Day 8 | 1.22 hours |
| Dose Escalation: TAK-981 120 mg | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981 | Cycle 1 Day 1 | 1.20 hours |
| Dose Escalation: TAK-981 120 mg | Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981 | Cycle 1 Day 8 | 1.28 hours |
Secondary
Phase 1: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981
Time frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours)
Population: PK Analysis Set included participants with sufficient dosing and PK data to reliably estimate 1 or more PK parameters. Overall number of participants analyzed is the number of participants with data available for analysis. Number of participants analyzed is the number of participants available for analysis during the specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 1: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981 | Cycle 1 Day 8 | 323 liters (L) | Standard Deviation 178 |
| Dose Escalation: TAK-981 40 mg | Phase 1: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981 | Cycle 1 Day 1 | 312 liters (L) | Standard Deviation 203 |
| Dose Escalation: TAK-981 60 mg | Phase 1: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981 | Cycle 1 Day 1 | 181 liters (L) | Standard Deviation 56.9 |
| Dose Escalation: TAK-981 60 mg | Phase 1: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981 | Cycle 1 Day 8 | 314 liters (L) | Standard Deviation 109 |
| Dose Escalation: TAK-981 90 mg | Phase 1: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981 | Cycle 1 Day 8 | 300 liters (L) | Standard Deviation 129 |
| Dose Escalation: TAK-981 90 mg | Phase 1: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981 | Cycle 1 Day 1 | 240 liters (L) | Standard Deviation 115 |
| Dose Escalation: TAK-981 120 mg | Phase 1: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981 | Cycle 1 Day 8 | 271 liters (L) | Standard Deviation 150 |
| Dose Escalation: TAK-981 120 mg | Phase 1: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981 | Cycle 1 Day 1 | 240 liters (L) | Standard Deviation 98.5 |
Secondary
Phase 2: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs)
An AE means any untoward medical occurrence in a participant administered a pharmaceutical product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product whether or not it is related to the medicinal product. A TEAE was defined as an adverse event which occurred on or after the first dose of study drug and no more than 30 days after the last dose of study drug. A severity grade was evaluated as per the NCI CTCAE Version 5.0, except for CRS, which was assessed by ASTCT Consensus Grading for CRS.
Time frame: Up to approximately 25 months
Population: Safety Analysis Set included participants who received at least 1 dose, even if incomplete, of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 2: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) | 7 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 2: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) | 5 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 2: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) | 18 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 2: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) | 8 Participants |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phase 2: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) | 14 Participants |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phase 2: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) | 4 Participants |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phase 2: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) | 2 Participants |
Secondary
Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation
An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.
Time frame: Up to approximately 25 months
Population: Safety Analysis Set included participants who received at least 1 dose, even if incomplete, of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of TAK-981 | 11 Participants |
| Dose Escalation: TAK-981 40 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of Pembrolizumab | 1 Participants |
| Dose Escalation: TAK-981 40 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of TAK-981 | 1 Participants |
| Dose Escalation: TAK-981 40 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of Pembrolizumab | 7 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of Pembrolizumab | 5 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of Pembrolizumab | 3 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of TAK-981 | 6 Participants |
| Dose Escalation: TAK-981 60 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of TAK-981 | 1 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of Pembrolizumab | 4 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of Pembrolizumab | 12 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of TAK-981 | 6 Participants |
| Dose Escalation: TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of TAK-981 | 15 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of Pembrolizumab | 4 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of TAK-981 | 5 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of TAK-981 | 0 Participants |
| Dose Escalation: TAK-981 120 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of Pembrolizumab | 0 Participants |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of Pembrolizumab | 3 Participants |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of Pembrolizumab | 13 Participants |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of TAK-981 | 15 Participants |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of TAK-981 | 6 Participants |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of TAK-981 | 6 Participants |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of TAK-981 | 1 Participants |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of Pembrolizumab | 2 Participants |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of Pembrolizumab | 1 Participants |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of Pembrolizumab | 0 Participants |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of TAK-981 | 4 Participants |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Dose Modifications of Pembrolizumab | 4 Participants |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phase 2: Number of Participants With One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation | TEAE Resulting in Drug Discontinuation of TAK-981 | 0 Participants |
Secondary
Phase 2: Overall Survival (OS)
OS is defined as the time from the date of the first dose administration to the date of death. Participants without documentation of death at the time of analysis were censored at the date last known to be alive.
Time frame: Up to approximately 25 months
Population: Response-Evaluable Analysis Set included participants who had received at least 1 dose of study drug, had sites of measurable disease at baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happened. Overall number of participants analyzed is the number of participants with events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 2: Overall Survival (OS) | NA months |
| Dose Escalation: TAK-981 60 mg | Phase 2: Overall Survival (OS) | 10.12 months |
| Dose Escalation: TAK-981 90 mg | Phase 2: Overall Survival (OS) | 14.55 months |
| Dose Escalation: TAK-981 120 mg | Phase 2: Overall Survival (OS) | NA months |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phase 2: Overall Survival (OS) | NA months |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phase 2: Overall Survival (OS) | NA months |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phase 2: Overall Survival (OS) | NA months |
Secondary
Phase 2: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs)
An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy. AEs were evaluated according to NCI CTCAE, Version 5.0 except CRS, which was graded according to ASTCT Consensus Grading for CRS.
Time frame: Up to approximately 25 months
Population: Safety Analysis Set included participants who received at least 1 dose, even if incomplete, of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phase 2: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Dose Escalation: TAK-981 60 mg | Phase 2: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Dose Escalation: TAK-981 90 mg | Phase 2: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Dose Escalation: TAK-981 120 mg | Phase 2: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phase 2: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phase 2: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs) | 93.3 percentage of participants |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phase 2: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs) | 100 percentage of participants |
Secondary
Phases 1 and 2: Disease Control Rate (DCR)
DCR is defined as the percentage of participants who achieved stable disease (SD) or better (CR + PR + SD determined by the investigator) \>6 weeks during the trial in the response-evaluable population.
Time frame: Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Population: Response-Evaluable Analysis Set included participants who had received at least 1 dose of study drug, had sites of measurable disease at baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happened.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phases 1 and 2: Disease Control Rate (DCR) | 33.3 percentage of participants |
| Dose Escalation: TAK-981 60 mg | Phases 1 and 2: Disease Control Rate (DCR) | 50.0 percentage of participants |
| Dose Escalation: TAK-981 90 mg | Phases 1 and 2: Disease Control Rate (DCR) | 30.3 percentage of participants |
| Dose Escalation: TAK-981 120 mg | Phases 1 and 2: Disease Control Rate (DCR) | 44.4 percentage of participants |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phases 1 and 2: Disease Control Rate (DCR) | 80.0 percentage of participants |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Disease Control Rate (DCR) | 62.5 percentage of participants |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Disease Control Rate (DCR) | 55.0 percentage of participants |
| Dose Expansion: Cohort C: MSS-CRC TAK-981 90 mg | Phases 1 and 2: Disease Control Rate (DCR) | 22.2 percentage of participants |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phases 1 and 2: Disease Control Rate (DCR) | 67.9 percentage of participants |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Disease Control Rate (DCR) | 30.8 percentage of participants |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Disease Control Rate (DCR) | 0 percentage of participants |
Secondary
Phases 1 and 2: Durable Response Rate (DRR)
DRR is defined as the rate of objective responses (CR + PR) maintained for at least 6 months initiating at any time within 12 months of commencing therapy.
Time frame: Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Population: Response-Evaluable Analysis Set included participants who had received at least 1 dose of study drug, had sites of measurable disease at baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happened.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phases 1 and 2: Durable Response Rate (DRR) | 0 percentage of participants |
| Dose Escalation: TAK-981 60 mg | Phases 1 and 2: Durable Response Rate (DRR) | 16.7 percentage of participants |
| Dose Escalation: TAK-981 90 mg | Phases 1 and 2: Durable Response Rate (DRR) | 6.1 percentage of participants |
| Dose Escalation: TAK-981 120 mg | Phases 1 and 2: Durable Response Rate (DRR) | 0 percentage of participants |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phases 1 and 2: Durable Response Rate (DRR) | 10.0 percentage of participants |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Durable Response Rate (DRR) | 0 percentage of participants |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Durable Response Rate (DRR) | 0 percentage of participants |
| Dose Expansion: Cohort C: MSS-CRC TAK-981 90 mg | Phases 1 and 2: Durable Response Rate (DRR) | 0 percentage of participants |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phases 1 and 2: Durable Response Rate (DRR) | 10.7 percentage of participants |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Durable Response Rate (DRR) | 0 percentage of participants |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Durable Response Rate (DRR) | 0 percentage of participants |
Secondary
Phases 1 and 2: Duration of Response (DOR)
DOR is defined as a time from the time of first documentation of tumor response to the first recorded occurrence of disease progression (PD) or death from any cause (whichever occurs first), through end of study.
Time frame: Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Population: Response-Evaluable Analysis Set included participants who had received at least 1 dose of study drug, had sites of measurable disease at baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happened. Overall number of participants analyzed is the number of participants with events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: TAK-981 60 mg | Phases 1 and 2: Duration of Response (DOR) | 17.12 hours |
| Dose Escalation: TAK-981 90 mg | Phases 1 and 2: Duration of Response (DOR) | 7.39 hours |
| Dose Escalation: TAK-981 120 mg | Phases 1 and 2: Duration of Response (DOR) | 3.71 hours |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phases 1 and 2: Duration of Response (DOR) | 7.62 hours |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Duration of Response (DOR) | NA hours |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phases 1 and 2: Duration of Response (DOR) | NA hours |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Duration of Response (DOR) | 4.34 hours |
Secondary
Phases 1 and 2: Progression-free Survival (PFS)
PFS is defined as time from the date of the first dose administration to the date of first documentation of PD or death due to any cause whichever occurs first, through the end of the study.
Time frame: Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Population: Response-Evaluable Analysis Set included participants who had received at least 1 dose of study drug, had sites of measurable disease at baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happened. Overall number of participants analyzed is the number of participants with events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phases 1 and 2: Progression-free Survival (PFS) | 2.00 months |
| Dose Escalation: TAK-981 60 mg | Phases 1 and 2: Progression-free Survival (PFS) | 4.21 months |
| Dose Escalation: TAK-981 90 mg | Phases 1 and 2: Progression-free Survival (PFS) | 1.99 months |
| Dose Escalation: TAK-981 120 mg | Phases 1 and 2: Progression-free Survival (PFS) | 2.11 months |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phases 1 and 2: Progression-free Survival (PFS) | 3.71 months |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Progression-free Survival (PFS) | 4.59 months |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Progression-free Survival (PFS) | 4.14 months |
| Dose Expansion: Cohort C: MSS-CRC TAK-981 90 mg | Phases 1 and 2: Progression-free Survival (PFS) | 1.64 months |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phases 1 and 2: Progression-free Survival (PFS) | 8.97 months |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Progression-free Survival (PFS) | 2.07 months |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Progression-free Survival (PFS) | 1.28 months |
Secondary
Phases 1 and 2: Time to Progression (TTP)
TTP is defined as the from the date of the first dose administration to the date of the first documentation of PD as defined by standard disease criteria.
Time frame: Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Population: Response-Evaluable Analysis Set included participants who had received at least 1 dose of study drug, had sites of measurable disease at baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happened. Overall number of participants analyzed is the number of participants with events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: TAK-981 40 mg | Phases 1 and 2: Time to Progression (TTP) | 2.00 months |
| Dose Escalation: TAK-981 60 mg | Phases 1 and 2: Time to Progression (TTP) | 4.21 months |
| Dose Escalation: TAK-981 90 mg | Phases 1 and 2: Time to Progression (TTP) | 2.07 months |
| Dose Escalation: TAK-981 120 mg | Phases 1 and 2: Time to Progression (TTP) | 2.07 months |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phases 1 and 2: Time to Progression (TTP) | 3.71 months |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Time to Progression (TTP) | 4.01 months |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Time to Progression (TTP) | 5.34 months |
| Dose Expansion: Cohort C: MSS-CRC TAK-981 90 mg | Phases 1 and 2: Time to Progression (TTP) | 1.76 months |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phases 1 and 2: Time to Progression (TTP) | 9.17 months |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Time to Progression (TTP) | 2.07 months |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Time to Progression (TTP) | 1.28 months |
Secondary
Phases 1 and 2: Time to Response (TTR)
TTR is defined as time from the date of the first dose administration to the date of first documented PR or better.
Time frame: Phase 1: Up to approximately 24 months, Phase 2: Up to approximately 25 months
Population: Response-Evaluable Analysis Set included participants who had received at least 1 dose of study drug, had sites of measurable disease at baseline, and 1 postbaseline disease assessment, or were discontinued due to symptomatic deterioration or death before a postbaseline evaluation happened. Overall number of participants analyzed is the number of participants with events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: TAK-981 60 mg | Phases 1 and 2: Time to Response (TTR) | 4.17 months |
| Dose Escalation: TAK-981 90 mg | Phases 1 and 2: Time to Response (TTR) | NA months |
| Dose Escalation: TAK-981 120 mg | Phases 1 and 2: Time to Response (TTR) | NA months |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phases 1 and 2: Time to Response (TTR) | 4.01 months |
| Dose Expansion: Cohort F: CPI Refractory Squamous and Non-squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Time to Response (TTR) | 6.01 months |
| Dose Expansion: Cohort D: Cutaneous Melanoma TAK-981 90 mg | Phases 1 and 2: Time to Response (TTR) | NA months |
| Dose Expansion: Cohort E: Squamous NSCLC TAK-981 90 mg | Phases 1 and 2: Time to Response (TTR) | NA months |