Advanced Nonhematologic Malignancies
Conditions
Keywords
Drug therapy
Brief summary
The primary purpose of this study is to determine the safety profile and the maximum tolerated doses (MTDs)/ potential recommended phase 2 doses (RP2Ds) of the combination treatments of MLN2480 + MLN0128, MLN2480 + alisertib, MLN2480 + paclitaxel, MLN2480 + cetuximab, and MLN2480 + irinotecan in participants with advanced nonhematologic malignancies.
Detailed description
The drug being tested in this study is called MLN2480 (TAK-580). MLN2480 was tested to evaluate side effects and determine the maximum tolerated dose (MTD) and recommended dose for future studies when administered in combination with five other medications. This study was to assess the safety of MLN2480 as well as how it is processed by the body in participants with solid nonhematologic malignancies who have failed standard therapies. The study was to be conducted in two phases, the dose escalation phase and the dose expansion phase. A total of 71 participants were enrolled in the escalation phase. Participants in this phase were assigned to one of the five treatment groups: * MLN2480 + MLN0128 * MLN2480 + Alisertib * MLN2480 + Paclitaxel * MLN2480 + Cetuximab * MLN2480 + Irinotecan Once the MTD for each combination treatment arm was established in the escalation phase, one or more of the combination treatments will be selected for the expansion phase. A total of 10 participants were enrolled in the expansion phase. This multi-centre trial was be conducted worldwide. The overall time to participate in this study is approximately 14 months. Participants made multiple visits to the clinic including an end of study visit 30 days after last dose of study drug for a follow-up assessment.
Interventions
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
All Treatment Arms: 1. Male or female participants 18 years or older. 2. Participants who, in the opinion of the treating physician, have failed standard therapies and for whom a phase 1 trial is an appropriate option. 3. Radiographically or clinically evaluable tumor. For expansion phase: Tumors must be measurable and of the protocol specified genetic mutational status, where applicable. 4. Recovered (ie, less than or equal to \[\<=\] Grade 1 toxicity) from adverse effects (except alopecia) of prior therapy. 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 6. Expected survival time of at least 3 months in the opinion of the investigator. 7. Block of banked tumor tissue and/or greater than or equal to (\>=) 10 unstained slides. Participants who satisfy all other eligibility criteria but do not have banked tissue/slides may be asked to consent to baseline biopsy. 8. Suitable vein access for the study-required blood sampling. 9. Thyroid function tests consistent with stable thyroid function. Note: Participants on a stable dose of thyroid replacement therapy for a suggested minimum of 12 weeks before Cycle 1, Day 1 are eligible. 10. Left ventricular ejection fraction (LVEF) of 50 percent (%) or greater, as measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA), within 28 days before the first dose of MLN2480 11. Female participants who are post-menopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 120 days (4 months) after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3 and 4, or agree to practice true abstinence. 12. Male participants who, even if surgically sterilized, agree to practice effective barrier contraception through 120 days (4 months) after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3, and 4, or agree to practice true abstinence. 13. Additional inclusion criteria for arm 3 expansion only (MLN2480 + paclitaxel): a. Participants with Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2 or BRAF non-V600 mutation-positive non-small cell lung cancer (NSCLC) who have received a minimum of 1 but not more than 2 prior cytotoxic-approved regimens. 14. Additional inclusion criteria for arms 4 and 5 expansion only (MLN2480 + cetuximab; MLN2480 + irinotecan): 1. Participants with CRC who have received a minimum of 1 but not more than 2 prior cytotoxic-approved regimens.
Exclusion criteria
All treatment arms: 1. Female participants who are pregnant or currently breastfeeding. 2. History of any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with safe protocol completion. 3. History of uncontrolled brain metastasis unless: previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery; stable disease for \>= 60 days without steroid use (or stable steroid dose established for \>= 28 days before the first dose of MLN2480). 4. Ongoing seizure disorder or a requirement for antiepileptics. 5. Recent prior therapies, including: chemotherapy and hormonal therapy \<= 4 weeks or 4 half lives, whichever occurs first, before administration of study drug; immunotherapy/monoclonal antibody use \<= 4 weeks before administration of MLN2480; or radiation therapy \<= 3 weeks before administration of study drug. 6. Chronic therapeutic corticosteroid use with the exception of replacement therapy for adrenal insufficiency or corticosteroid inhalers. 7. Known history of human immunodeficiency virus infection, hepatitis B, or hepatitis C; Prior allogeneic bone marrow or organ transplantation, or active condition of chronic immune suppression is not allowed. 8. Concomitant use, or administration \<= 14 days before first dose of study drug(s), of clinically significant enzyme inducers. 9. Treatment with gemfibrozil (strong Cytochrome P4502C8 \[CYP2C8\] inhibitor) within 14 days before the first dose of MLN2480. 10. History of or current illicit drug use, drug abuse, or alcohol abuse. 11. Major surgery within 14 days before the first dose of study drug. 12. Inability to comply with study requirements. 13. Other unspecified reasons that, in the opinion of the investigator or Millennium, make the participant unsuitable for enrollment. 14. Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months) | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An SAE means any untoward medical occurrence that at any dose results in death, is life-threatening, requires in patient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. |
| Number of Participants With Dose-Limiting Toxicities (DLTs) | From Day 1, Cycle 1 through 30 days after the last dose in Cycle 1 (up to 8 weeks) | DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia \<7 days duration; Grade 3 or 4 neutropenia with fever \>38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity resulted in delay in initiation of Cycle 2. |
| Maximum Tolerated Dose (MTD) for MLN2480 | Day 1, Cycle 1 up to 28 days | — |
| Recommended Phase 2 Dose (RP2D) of MLN2480 | Day 1, Cycle 1 up to 28 days | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax: Maximum Observed Plasma Concentration for Alisertib | Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose | — |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN2480 | Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose | — |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose | — |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib | Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose | — |
| AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN2480 | Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose | — |
| AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN0128 | Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose | — |
| Cmax: Maximum Observed Plasma Concentration for Paclitaxel | Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose | — |
| AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel | Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose | — |
| Terminal Elimination Half-life (T1/2) for Paclitaxel | Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose | — |
| Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Up to 13 months) | ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. |
| Duration of Response | From first documented response until disease progression (Up to 13 months) | Duration of Response (DOR) was defined as the time in months from the first documented CR or PR per RECIST v. 1.1 to disease recurrence or disease progression (PD) whichever occurs first. |
| Time to Response | From date of enrollment to the date of the first documentation of a confirmed response (Up to 13 months) | Time to response was defined as the time in months from the date of first dose of study treatment to the date of the first documentation of a PR or better response. |
| Progression Free Survival (PFS) | Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Approximately up to 13 months) | PFS is defined as the time in months from the date of first study drug administration to the date of first documented PD or death due to any cause. PD was based on response evaluation criteria in solid tumors (RECIST V1.1), defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib | Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose | — |
| AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel | Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose | — |
| Cmax : Maximum Observed Plasma Concentration for MLN2480 | Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose | — |
| Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose | — |
Countries
France, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 14 investigative sites in the United States, France, Spain, and United Kingdom from 14 September 2016 to 02 July 2018.
Pre-assignment details
Participants with a diagnosis of advanced nonhematologic malignancies were enrolled in one of the five arm groups: MLN2480 + MLN0128, MLN2480 + Alisertib, MLN2480 + Paclitaxel, MLN2480 + Cetuximab, MLN2480 + Irinotecan.
Participants by arm
| Arm | Count |
|---|---|
| MLN2480 100 mg + MLN0128 2 mg Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. | 4 |
| MLN2480 100 mg + Alisertib 30 mg Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. | 3 |
| MLN2480 160 mg + Alisertib 30 mg Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. | 7 |
| MLN2480 200 mg + Alisertib 30 mg Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. | 3 |
| MLN2480 100 mg + Alisertib 40 mg Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. | 8 |
| MLN2480 100 mg + Paclitaxel 80 mg/m^2 Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m\^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. | 4 |
| MLN2480 160 mg + Paclitaxel 80 mg/m^2 Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m\^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. | 3 |
| MLN2480 200 mg + Paclitaxel 80 mg/m^2 Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m\^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. | 4 |
| MLN2480 400 mg + Paclitaxel 80 mg/m^2 Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m\^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. | 6 |
| MLN2480 600 mg + Paclitaxel 80 mg/m^2 Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m\^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. | 8 |
| MLN2480 400 mg + Cetuximab 250 mg/m^2 Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m\^2 (cycle 1 Day 1), then at 250 mg/m\^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. | 6 |
| MLN2480 600 mg + Cetuximab 250 mg/m^2 Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m\^2 (cycle 1 Day 1), then at 250 mg/m\^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. | 7 |
| ML2480 300 mg + Irinotecan 180 mg/m^2 Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m\^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. | 1 |
| ML2480 400 mg + Irinotecan 180 mg/m^2 Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m\^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. | 7 |
| Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m\^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles. | 10 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 2 | 0 | 3 | 0 | 2 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Progressive Disease | 1 | 3 | 4 | 3 | 4 | 3 | 3 | 3 | 4 | 4 | 4 | 3 | 1 | 3 | 3 |
| Overall Study | Reason Not Specified | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 | 1 | 0 | 0 | 2 |
| Overall Study | Symptomatic Deterioration | 0 | 0 | 1 | 0 | 1 | 1 | 0 | 0 | 2 | 1 | 0 | 0 | 0 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | MLN2480 100 mg + Alisertib 30 mg | MLN2480 160 mg + Alisertib 30 mg | MLN2480 200 mg + Alisertib 30 mg | MLN2480 100 mg + Alisertib 40 mg | MLN2480 100 mg + Paclitaxel 80 mg/m^2 | MLN2480 160 mg + Paclitaxel 80 mg/m^2 | MLN2480 200 mg + Paclitaxel 80 mg/m^2 | MLN2480 400 mg + Paclitaxel 80 mg/m^2 | MLN2480 600 mg + Paclitaxel 80 mg/m^2 | MLN2480 400 mg + Cetuximab 250 mg/m^2 | MLN2480 600 mg + Cetuximab 250 mg/m^2 | ML2480 300 mg + Irinotecan 180 mg/m^2 | ML2480 400 mg + Irinotecan 180 mg/m^2 | Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 | MLN2480 100 mg + MLN0128 2 mg | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 48.0 years | 60.9 years | 51.0 years | 68.0 years | 66.0 years | 60.3 years | 70.0 years | 54.2 years | 65.9 years | 52.8 years | 60.1 years | 62.0 years | 62.3 years | 63.9 years | 57.5 years | 62.3 years |
| Body Surface Area (BSA) | 1.906 square meters (m^2) | 1.961 square meters (m^2) | 1.817 square meters (m^2) | 1.698 square meters (m^2) | 2.003 square meters (m^2) | 1.884 square meters (m^2) | 1.732 square meters (m^2) | 1.726 square meters (m^2) | 1.738 square meters (m^2) | 1.893 square meters (m^2) | 1.814 square meters (m^2) | 2.094 square meters (m^2) | 1.925 square meters (m^2) | 1.740 square meters (m^2) | 1.818 square meters (m^2) | 1.846 square meters (m^2) |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 7 Participants | 0 Participants | 8 Participants | 3 Participants | 1 Participants | 4 Participants | 5 Participants | 7 Participants | 5 Participants | 4 Participants | 1 Participants | 7 Participants | 6 Participants | 4 Participants | 65 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 4 Participants | 0 Participants | 14 Participants |
| Height | 163.4 centimetres (cm) | 166.7 centimetres (cm) | 160.3 centimetres (cm) | 164.5 centimetres (cm) | 167.0 centimetres (cm) | 167.7 centimetres (cm) | 166.3 centimetres (cm) | 159.7 centimetres (cm) | 167.3 centimetres (cm) | 169.8 centimetres (cm) | 167.4 centimetres (cm) | 182.5 centimetres (cm) | 172.3 centimetres (cm) | 162.7 centimetres (cm) | 168.9 centimetres (cm) | 164.7 centimetres (cm) |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 4 Participants | 0 Participants | 12 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 6 Participants | 1 Participants | 8 Participants | 4 Participants | 2 Participants | 4 Participants | 3 Participants | 6 Participants | 6 Participants | 4 Participants | 1 Participants | 7 Participants | 5 Participants | 4 Participants | 64 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 1 Participants | 6 Participants | 2 Participants | 2 Participants | 3 Participants | 5 Participants | 4 Participants | 2 Participants | 4 Participants | 0 Participants | 3 Participants | 5 Participants | 3 Participants | 47 Participants |
| Sex: Female, Male Male | 0 Participants | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants | 4 Participants | 3 Participants | 1 Participants | 4 Participants | 5 Participants | 1 Participants | 34 Participants |
| Weight | 80.53 kilograms (kg) | 84.62 kilograms (kg) | 74.15 kilograms (kg) | 63.59 kilograms (kg) | 86.63 kilograms (kg) | 77.40 kilograms (kg) | 65.45 kilograms (kg) | 67.92 kilograms (kg) | 65.79 kilograms (kg) | 76.22 kilograms (kg) | 71.39 kilograms (kg) | 86.50 kilograms (kg) | 74.97 kilograms (kg) | 67.65 kilograms (kg) | 71.55 kilograms (kg) | 70.31 kilograms (kg) |
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 | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 | 2 / 7 | 0 / 3 | 1 / 8 | 0 / 4 | 0 / 3 | 0 / 4 | 0 / 6 | 0 / 8 | 2 / 6 | 2 / 7 | 0 / 1 | 0 / 7 | 2 / 10 |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 7 / 7 | 3 / 3 | 8 / 8 | 4 / 4 | 3 / 3 | 4 / 4 | 6 / 6 | 8 / 8 | 6 / 6 | 7 / 7 | 1 / 1 | 7 / 7 | 10 / 10 |
| serious Total, serious adverse events | 2 / 4 | 1 / 3 | 5 / 7 | 1 / 3 | 3 / 8 | 1 / 4 | 1 / 3 | 2 / 4 | 3 / 6 | 4 / 8 | 2 / 6 | 3 / 7 | 0 / 1 | 4 / 7 | 7 / 10 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) for MLN2480
Time frame: Day 1, Cycle 1 up to 28 days
Population: The DLT-evaluable population was defined as all participants in the dose escalation phase of the study who either experienced DLT during cycle 1, or completed at least 75% of the scheduled doses in cycle 1 without DLT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN2480 100 mg + MLN0128 2 mg | Maximum Tolerated Dose (MTD) for MLN2480 | NA mg |
| MLN2480 100 mg + Alisertib 30 mg | Maximum Tolerated Dose (MTD) for MLN2480 | NA mg |
| MLN2480 160 mg + Alisertib 30 mg | Maximum Tolerated Dose (MTD) for MLN2480 | NA mg |
| MLN2480 200 mg + Alisertib 30 mg | Maximum Tolerated Dose (MTD) for MLN2480 | NA mg |
| MLN2480 100 mg + Alisertib 40 mg | Maximum Tolerated Dose (MTD) for MLN2480 | NA mg |
| MLN2480 100 mg + Paclitaxel 80 mg/m^2 | Maximum Tolerated Dose (MTD) for MLN2480 | NA mg |
| MLN2480 160 mg + Paclitaxel 80 mg/m^2 | Maximum Tolerated Dose (MTD) for MLN2480 | NA mg |
| MLN2480 200 mg + Paclitaxel 80 mg/m^2 | Maximum Tolerated Dose (MTD) for MLN2480 | NA mg |
| MLN2480 400 mg + Paclitaxel 80 mg/m^2 | Maximum Tolerated Dose (MTD) for MLN2480 | NA mg |
| MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Maximum Tolerated Dose (MTD) for MLN2480 | 600 mg |
| MLN2480 400 mg + Cetuximab 250 mg/m^2 | Maximum Tolerated Dose (MTD) for MLN2480 | NA mg |
| MLN2480 600 mg + Cetuximab 250 mg/m^2 | Maximum Tolerated Dose (MTD) for MLN2480 | NA mg |
| ML2480 300 mg + Irinotecan 180 mg/m^2 | Maximum Tolerated Dose (MTD) for MLN2480 | NA mg |
| ML2480 400 mg + Irinotecan 180 mg/m^2 | Maximum Tolerated Dose (MTD) for MLN2480 | NA mg |
| Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Maximum Tolerated Dose (MTD) for MLN2480 | NA mg |
Primary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An SAE means any untoward medical occurrence that at any dose results in death, is life-threatening, requires in patient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.
Time frame: From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months)
Population: Safety population was defined as all participants who received any amount of MLN2480.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MLN2480 100 mg + MLN0128 2 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 4 Participants |
| MLN2480 100 mg + MLN0128 2 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| MLN2480 100 mg + Alisertib 30 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| MLN2480 100 mg + Alisertib 30 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| MLN2480 160 mg + Alisertib 30 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 7 Participants |
| MLN2480 160 mg + Alisertib 30 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 5 Participants |
| MLN2480 200 mg + Alisertib 30 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| MLN2480 200 mg + Alisertib 30 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| MLN2480 100 mg + Alisertib 40 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 3 Participants |
| MLN2480 100 mg + Alisertib 40 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 8 Participants |
| MLN2480 100 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| MLN2480 100 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 4 Participants |
| MLN2480 160 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| MLN2480 160 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| MLN2480 200 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 4 Participants |
| MLN2480 200 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| MLN2480 400 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 6 Participants |
| MLN2480 400 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 3 Participants |
| MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 4 Participants |
| MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 8 Participants |
| MLN2480 400 mg + Cetuximab 250 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 6 Participants |
| MLN2480 400 mg + Cetuximab 250 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| MLN2480 600 mg + Cetuximab 250 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 3 Participants |
| MLN2480 600 mg + Cetuximab 250 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 7 Participants |
| ML2480 300 mg + Irinotecan 180 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| ML2480 300 mg + Irinotecan 180 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 1 Participants |
| ML2480 400 mg + Irinotecan 180 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 7 Participants |
| ML2480 400 mg + Irinotecan 180 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 4 Participants |
| Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 7 Participants |
| Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 10 Participants |
Primary
Number of Participants With Dose-Limiting Toxicities (DLTs)
DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia \<7 days duration; Grade 3 or 4 neutropenia with fever \>38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity resulted in delay in initiation of Cycle 2.
Time frame: From Day 1, Cycle 1 through 30 days after the last dose in Cycle 1 (up to 8 weeks)
Population: The DLT-evaluable population was defined as all participants in the dose escalation phase of the study who either experienced DLT during cycle 1, or completed at least 75% of the scheduled doses in cycle 1 without DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MLN2480 100 mg + MLN0128 2 mg | Number of Participants With Dose-Limiting Toxicities (DLTs) | 1 Participants |
| MLN2480 100 mg + Alisertib 30 mg | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| MLN2480 160 mg + Alisertib 30 mg | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| MLN2480 200 mg + Alisertib 30 mg | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| MLN2480 100 mg + Alisertib 40 mg | Number of Participants With Dose-Limiting Toxicities (DLTs) | 1 Participants |
| MLN2480 100 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| MLN2480 160 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| MLN2480 200 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| MLN2480 400 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Dose-Limiting Toxicities (DLTs) | 1 Participants |
| MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Dose-Limiting Toxicities (DLTs) | 1 Participants |
| MLN2480 400 mg + Cetuximab 250 mg/m^2 | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| MLN2480 600 mg + Cetuximab 250 mg/m^2 | Number of Participants With Dose-Limiting Toxicities (DLTs) | 1 Participants |
| ML2480 300 mg + Irinotecan 180 mg/m^2 | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| ML2480 400 mg + Irinotecan 180 mg/m^2 | Number of Participants With Dose-Limiting Toxicities (DLTs) | 1 Participants |
| Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Number of Participants With Dose-Limiting Toxicities (DLTs) | 1 Participants |
Primary
Recommended Phase 2 Dose (RP2D) of MLN2480
Time frame: Day 1, Cycle 1 up to 28 days
Population: The DLT-evaluable population was defined as all participants in the dose escalation phase of the study who either experienced DLT during cycle 1, or completed at least 75% of the scheduled doses in cycle 1 without DLT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN2480 100 mg + MLN0128 2 mg | Recommended Phase 2 Dose (RP2D) of MLN2480 | NA mg |
| MLN2480 100 mg + Alisertib 30 mg | Recommended Phase 2 Dose (RP2D) of MLN2480 | NA mg |
| MLN2480 160 mg + Alisertib 30 mg | Recommended Phase 2 Dose (RP2D) of MLN2480 | NA mg |
| MLN2480 200 mg + Alisertib 30 mg | Recommended Phase 2 Dose (RP2D) of MLN2480 | NA mg |
| MLN2480 100 mg + Alisertib 40 mg | Recommended Phase 2 Dose (RP2D) of MLN2480 | NA mg |
| MLN2480 100 mg + Paclitaxel 80 mg/m^2 | Recommended Phase 2 Dose (RP2D) of MLN2480 | NA mg |
| MLN2480 160 mg + Paclitaxel 80 mg/m^2 | Recommended Phase 2 Dose (RP2D) of MLN2480 | NA mg |
| MLN2480 200 mg + Paclitaxel 80 mg/m^2 | Recommended Phase 2 Dose (RP2D) of MLN2480 | NA mg |
| MLN2480 400 mg + Paclitaxel 80 mg/m^2 | Recommended Phase 2 Dose (RP2D) of MLN2480 | NA mg |
| MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Recommended Phase 2 Dose (RP2D) of MLN2480 | 600 mg |
| MLN2480 400 mg + Cetuximab 250 mg/m^2 | Recommended Phase 2 Dose (RP2D) of MLN2480 | NA mg |
| MLN2480 600 mg + Cetuximab 250 mg/m^2 | Recommended Phase 2 Dose (RP2D) of MLN2480 | NA mg |
| ML2480 300 mg + Irinotecan 180 mg/m^2 | Recommended Phase 2 Dose (RP2D) of MLN2480 | NA mg |
| ML2480 400 mg + Irinotecan 180 mg/m^2 | Recommended Phase 2 Dose (RP2D) of MLN2480 | NA mg |
| Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Recommended Phase 2 Dose (RP2D) of MLN2480 | NA mg |
Secondary
AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel
Time frame: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Population: The limited PK data did not allow to estimate the PK parameters defined in the protocol.
Secondary
AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel
Time frame: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Population: The limited PK data did not allow to estimate the PK parameters defined in the protocol.
Secondary
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Population: The limited PK data did not allow to estimate the PK parameters defined in the protocol.
Secondary
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN0128
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Population: The limited PK data did not allow to estimate the PK parameters defined in the protocol.
Secondary
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN2480
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Population: The limited PK data did not allow to estimate the PK parameters defined in the protocol.
Secondary
Cmax: Maximum Observed Plasma Concentration for Alisertib
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Population: The limited PK data did not allow to estimate the PK parameters defined in the protocol.
Secondary
Cmax: Maximum Observed Plasma Concentration for MLN0128
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Population: The limited PK data did not allow to estimate the PK parameters defined in the protocol.
Secondary
Cmax : Maximum Observed Plasma Concentration for MLN2480
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Population: The limited PK data did not allow to estimate the PK parameters defined in the protocol.
Secondary
Cmax: Maximum Observed Plasma Concentration for Paclitaxel
Time frame: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Population: The limited PK data did not allow to estimate the PK parameters defined in the protocol.
Secondary
Duration of Response
Duration of Response (DOR) was defined as the time in months from the first documented CR or PR per RECIST v. 1.1 to disease recurrence or disease progression (PD) whichever occurs first.
Time frame: From first documented response until disease progression (Up to 13 months)
Population: Responders from response-evaluable population was defined as participants who received at least 1 dose of study drug, had measurable disease at baseline, and 1 postbaseline response assessment. For a participant that has not progressed, DOR was censored at the last response assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MLN2480 100 mg + Alisertib 40 mg | Duration of Response | NA months |
| MLN2480 100 mg + Paclitaxel 80 mg/m^2 | Duration of Response | 3.7 months |
| MLN2480 400 mg + Paclitaxel 80 mg/m^2 | Duration of Response | 6.5 months |
| MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Duration of Response | 3.5 months |
| Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Duration of Response | 11.5 months |
Secondary
Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)
ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
Time frame: Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Up to 13 months)
Population: Response-evaluable population was defined as participants who received at least 1 dose of study drug, had measurable disease at baseline, and 1 postbaseline response assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN2480 100 mg + MLN0128 2 mg | Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 0 percentage of participants |
| MLN2480 100 mg + Alisertib 30 mg | Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 0 percentage of participants |
| MLN2480 160 mg + Alisertib 30 mg | Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 0 percentage of participants |
| MLN2480 200 mg + Alisertib 30 mg | Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 0 percentage of participants |
| MLN2480 100 mg + Alisertib 40 mg | Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 17 percentage of participants |
| MLN2480 100 mg + Paclitaxel 80 mg/m^2 | Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 75 percentage of participants |
| MLN2480 160 mg + Paclitaxel 80 mg/m^2 | Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 0 percentage of participants |
| MLN2480 200 mg + Paclitaxel 80 mg/m^2 | Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 0 percentage of participants |
| MLN2480 400 mg + Paclitaxel 80 mg/m^2 | Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 40 percentage of participants |
| MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 17 percentage of participants |
| MLN2480 400 mg + Cetuximab 250 mg/m^2 | Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 0 percentage of participants |
| MLN2480 600 mg + Cetuximab 250 mg/m^2 | Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 0 percentage of participants |
| ML2480 300 mg + Irinotecan 180 mg/m^2 | Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 0 percentage of participants |
| ML2480 400 mg + Irinotecan 180 mg/m^2 | Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 0 percentage of participants |
| Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 38 percentage of participants |
Secondary
Progression Free Survival (PFS)
PFS is defined as the time in months from the date of first study drug administration to the date of first documented PD or death due to any cause. PD was based on response evaluation criteria in solid tumors (RECIST V1.1), defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Approximately up to 13 months)
Population: Safety population is defined as all participants who received any amount of MLN2480. For a participant that has not progressed and has not died, PFS was censored at the last response assessment that is SD or better. Participants with no response assessment were censored at the date of first dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MLN2480 100 mg + MLN0128 2 mg | Progression Free Survival (PFS) | 0.5 months |
| MLN2480 100 mg + Alisertib 30 mg | Progression Free Survival (PFS) | 1.9 months |
| MLN2480 160 mg + Alisertib 30 mg | Progression Free Survival (PFS) | 3.7 months |
| MLN2480 200 mg + Alisertib 30 mg | Progression Free Survival (PFS) | 1.9 months |
| MLN2480 100 mg + Alisertib 40 mg | Progression Free Survival (PFS) | 9.5 months |
| MLN2480 100 mg + Paclitaxel 80 mg/m^2 | Progression Free Survival (PFS) | 5.3 months |
| MLN2480 160 mg + Paclitaxel 80 mg/m^2 | Progression Free Survival (PFS) | 5.5 months |
| MLN2480 200 mg + Paclitaxel 80 mg/m^2 | Progression Free Survival (PFS) | 2.9 months |
| MLN2480 400 mg + Paclitaxel 80 mg/m^2 | Progression Free Survival (PFS) | 7.6 months |
| MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Progression Free Survival (PFS) | 3.3 months |
| MLN2480 400 mg + Cetuximab 250 mg/m^2 | Progression Free Survival (PFS) | 2.2 months |
| MLN2480 600 mg + Cetuximab 250 mg/m^2 | Progression Free Survival (PFS) | 1.7 months |
| ML2480 300 mg + Irinotecan 180 mg/m^2 | Progression Free Survival (PFS) | 3.6 months |
| ML2480 400 mg + Irinotecan 180 mg/m^2 | Progression Free Survival (PFS) | 4.7 months |
| Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Progression Free Survival (PFS) | 5.7 months |
Secondary
Terminal Elimination Half-life (T1/2) for Paclitaxel
Time frame: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Population: The limited PK data did not allow to estimate the PK parameters defined in the protocol.
Secondary
Time to Response
Time to response was defined as the time in months from the date of first dose of study treatment to the date of the first documentation of a PR or better response.
Time frame: From date of enrollment to the date of the first documentation of a confirmed response (Up to 13 months)
Population: Response-evaluable population was defined as all participants with measurable disease at baseline who received any amount of MLN2480 and have at least 1 post baseline response assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MLN2480 100 mg + Alisertib 40 mg | Time to Response | 4.2 months |
| MLN2480 100 mg + Paclitaxel 80 mg/m^2 | Time to Response | 3.7 months |
| MLN2480 400 mg + Paclitaxel 80 mg/m^2 | Time to Response | 2.7 months |
| MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Time to Response | 1.8 months |
| Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 | Time to Response | 1.9 months |
Secondary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Population: The limited PK data did not allow to estimate the PK parameters defined in the protocol.
Secondary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Population: The limited PK data did not allow to estimate the PK parameters defined in the protocol.
Secondary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN2480
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Population: The limited PK data did not allow to estimate the PK parameters defined in the protocol.