Cancer, Solid Tumors
Conditions
Keywords
AKT1, AKT2, AKT3, PI3K, solid tumors, cancer, ARQ 751, PTEN
Brief summary
The primary objectives of this study are: Part 1 - Vevorisertib as single agent: To assess the safety and tolerability of vevorisertib in participants with advanced solid tumors with v-Akt murine thymoma viral oncogene homolog (AKT) 1, 2, 3 genetic alterations, activating phosphatidylinositol-3-kinase (PI3K) mutations, phosphatase and tensin homolog deleted on chromosome ten (PTEN)-null, or other known actionable PTEN mutations; Part 2 - Vevorisertib in combination with other anti-cancer agents: To assess the safety and tolerability of vevorisertib in combination with paclitaxel or fulvestrant in participants with advanced, inoperable, metastatic and/or recurrent solid tumors with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) / PTEN actionable mutations and/or AKT genetic alterations.
Detailed description
This study was terminated due to business reasons, and pharmacokinetic (PK) testing was prioritized.
Interventions
DRUGVevorisertib
Administered as an oral dose every day or every other day.
DRUGFulvestrant
Administered as an intramuscular (IM) injection.
DRUGPaclitaxel
Administered as an intravenous (IV) infusion.
Sponsors
ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed written informed consent granted prior to initiation of any study-specific procedures 2. 18 years of age and older 3. Histologically and/or cytologically documented diagnosis of a selected tumor type that is locally advanced, inoperable, metastatic or recurrent (including but not restricted to breast cancer, TNBC \[triple negative\]; HR-positive \[HR+\]/HER2-negative \[HER2-\] or endometrial cancer) 4. Documented AKT genetic alterations or known actionable PIK3CA/PTEN mutations by genetic testing • Participants with tumors with PTEN null/PTEN loss-of-function mutations are not eligible 5. For combination arms; participants should be eligible for paclitaxel or fulvestrant therapy as per Investigator assessment 6. Failure to respond to standard systemic therapy, or for whom standard or curative systemic therapy does not exist or is not tolerable * Participants in single agent arm (with AKT genetic alterations) and participants in dose escalation cohorts of combination therapy arms should have at least one line of standard systemic therapy * Participants in single agent arm (with PIK3CA/PTEN actionable mutations) and participants in the expansion cohorts of combination therapy arms should have no more than 3 prior systemic regimens for the advanced disease * Neoadjuvant and adjuvant chemotherapy are considered one regimen if they are a continuation of the same regimen with interval debulking surgery * If the participant is refractory or has disease progression within 6 months after completion of the adjuvant treatment, then the adjuvant treatment should be considered as the line of treatment rather than an adjuvant therapy. * Endocrine (hormonal) therapy does not count toward total lines of therapy * Maintenance therapy is considered part of the preceding regimen if one or more of the same drugs are continued 7. Has at least one measurable target lesion according to RECIST v. 1.1 8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1 9. Adequate organ function as indicated by the following laboratory values. (All laboratory tests must be obtained within 14 days prior to the first dose of study treatment): 1. Hematological * Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L * Platelet count (Plt) ≥ 100 x 10⁹/L * Hemoglobin (Hb) ≥ 9 g/dL * International normalized ratio (INR) 0.8 to upper limit of normal (ULN) or ≤ 3 for participants receiving anticoagulant therapy such as Coumadin or heparin 2. Renal * Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with serum creatinine levels \> 1.5 x institutional ULN 3. Hepatic * Total bilirubin ≤ 1.5 x ULN * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN or ≤ 5 x ULN for participants with known liver metastases 4. Metabolic * Glycated hemoglobin (HbA1c) ≤ 8% (≤ 64 mmol/mol) 10. If a participant is currently receiving bisphosphonates or any other drug for treatment of osteoporosis, treatment-induced bone loss and metastases to bone, the participant must have received the bisphosphonates for at least four weeks prior to the first dose of study treatment • Initiation of bisphosphonates or similar agents during the study may be allowed provided the participant completes the first cycle of treatment without any dose limiting toxicity (DLT) and the Investigator rules out tumor progression 11. Male or female participants of child-producing potential must agree to use adequate contraception, including double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after the last dose of study treatment 12. Women of childbearing potential must have a negative serum pregnancy test. Women of childbearing potential is defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months prior to the first dose of study treatment
Exclusion criteria
1. Anti-cancer therapy, such as chemotherapy, immunotherapy, hormonal therapy, targeted therapy, or investigational agents within five half-lives or four weeks, whichever is shorter, prior to administration of the first dose of study treatment * To be eligible for study treatment, toxicity from prior treatment(s) must recover to Grade ≤ 1, except for alopecia * Concurrent systemic high-dose corticosteroids (in dosing exceeding 10 mg QD of prednisone equivalent) when used intermittently in an antiemetic regimen, for central nervous system (CNS) metastases management, or as a part of the premedication regimen are allowed 2. Radiation therapy within four weeks, or palliative radiation therapy within two weeks, prior to administration of the first dose of study treatment * To be eligible for study treatment, radiation therapy-related toxicity must recover to Grade ≤ 1 prior to administration of the first dose of study treatment * Concurrent palliative radiotherapy for local pain-control or prevention of fracture (for known bone metastases) may be allowed provided the participant completes the first cycle of treatment, does not meet criteria of progressive disease, and treated lesions will not be included in the target/non-target lesion assessment 3. Major surgical procedure within four weeks prior to administration of the first dose of study treatment • To be eligible for the study treatment, all surgical wounds must be fully healed, and any surgery-related adverse events must recover to Grade ≤ 1. 4. Unable or unwilling to swallow the complete daily dose of vevorisertib 5. Previous treatment with * AKT inhibitors (e.g., ARQ 092, MK-2206, GSK2141795, AZD5363; prior treatment with PI3K or mammalian target of rapamycin (mTOR) inhibitor are allowed) * Prior taxane therapy for the advanced, metastatic disease (for participants considered for vevorisertib +paclitaxel combination arm only) 6. Known prior allergic reaction to or severe intolerance of paclitaxel or fulvestrant. Intolerance is defined as a serious adverse event (AE), a grade 3 or 4 AE per Common Terminology Criteria for Adverse Events (CTCAE) v.4.03, or permanent treatment discontinuation 7. History of Type 1 diabetes mellitus or Type 2 diabetes mellitus requiring regular medication (other than oral hypoglycemic agents) or fasting glucose ≥ 160 mg/dL at Screening visit 8. Significant gastrointestinal disorder(s) that could, in the opinion of the Investigator, interfere with the absorption, metabolism, or excretion of vevorisertib (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, extensive gastric resection) 9. Known untreated or active CNS metastases and/or carcinomatous meningitis • To be eligible for the study treatment, participants must have stable disease ≥ 1 month, confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and have CNS metastases well controlled by low-dose steroids, anti-epileptics, or other symptom-relieving medications 10. History of myocardial infarction (MI) or New York Heart Association (NYHA) Class II-IV congestive heart failure within 6 months of the administration of the first dose of study treatment (MI occurring \> 6 months of the first dose of study treatment will be permitted); Grade 2 or worse conduction defect (e.g., right or left bundle branch block) 11. A heart rate corrected QT (QTc) interval ≥ 480 msec, using the Fridericia's formula QTcF 12. Left ventricular ejection fraction (LVEF) \<50% as determined by Multiple Gated Acquisition (MUGA) scan or echocardiogram (ECHO) in participants who received prior treatment with anthracyclines 13. Concurrent severe and/or uncontrolled illness not related to cancer and/or social situation that would limit compliance with study requirements, including but not limited to: * Psychiatric illness, substance abuse * Ongoing or active known infection, including human immunodeficiency virus (HIV) infection, hepatitis B or C virus * Significant pulmonary dysfunction, including pneumonitis, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, cystic fibrosis, severe chronic obstructive pulmonary disease (COPD) * Peripheral neuropathy grade ≥2 (vevorisertib+paclitaxel combination arm) * Bleeding diathesis, thrombocytopenia or coagulation disorders (vevorisertib+fulvestrant combination arm) * Thrombotic/coagulation disorders within 6 months prior to the first dose of study treatment unless stable on anticoagulation for \> 3 months 14. Active or history of other malignancy other than the current cancer within 2 years of the first dose of study treatment, with the exception of carcinoma in-situ of the cervix, basal cell carcinoma, and superficial bladder tumors curatively treated 15. Blood transfusion or administration of growth factors within 5 days prior to a blood draw being used to confirm eligibility 16. Pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experience One or More Adverse Events (AEs) | Up to approximately 120 weeks | An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with study-drug treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE. |
| Number of Participants Who Discontinue Study Treatment Due to an AE | Up to approximately 116 weeks | An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with study-drug treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 1: predose, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 1 Day 22: predose, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 2 Day 1: predose. Cycle = 28 days. | t1/2 was defined as the terminal elimination half-life of drug. This study was terminated because of business reasons. Due to study termination, pharmacokinetic (PK) testing was prioritized for dosing arms and timepoints that would provide the required data to support programmatic decision-making and subsequent clinical studies. Zero participants analyzed entered in the table indicate data were not generated and no data were available. t1/2 is reported as geometric mean with a percent coefficient of variation. |
| Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | Cycle 1 (Up to approximately 28 days) | DLTs consisted of hematologic or non-hematologic toxicities. Hematologic DLT was any grade (Gr) 4 anemia, Gr 4 neutropenia, Gr 4 thrombocytopenia, Gr 3 lasting \>7 days, Gr 3 thrombocytopenia in the presence of bleeding, or ≥ Gr 3 hyperglycemia. Non-hematologic DLT was any Gr 3, 4 or 5 non-hematologic toxicity with the exception of: (1) Gr 3 nausea, vomiting, diarrhea or responding to optimal medical management within 48 hours; (2) alopecia. Per protocol DLTs were analyzed in the first 28-day treatment cycle. The number of participants experiencing DLTs is reported here for all participants who got ≥1 dose of study drug. |
| Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 1: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 1 Day 22: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 2 Day 1: predose. Cycle = 28 days. | Cmax was defined as the maximum plasma drug concentration. This study was terminated because of business reasons. Due to study termination, pharmacokinetic (PK) testing was prioritized for dosing arms and timepoints that would provide the required data to support programmatic decision-making and subsequent clinical studies. Zero participants analyzed entered in the table indicate data were not generated and no data were available. Cmax is reported as geometric mean with a percent coefficient of variation. |
| Best Overall Response (BOR) | Up to approximately 116 weeks | BOR was assessed using RECIST 1.1. Response categories included: CR: disappearance of all target lesions; PR: at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD; Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; and Inevaluable: participants who have SD as their best overall response but fail to achieve the protocol-defined duration for SD. Percentage of participants with CR, PR, SD, PD, or inevaluable as a best overall response have been reported. |
| Disease Control Rate (DCR) | Up to approximately 116 weeks | DCR was defined, per RECIST 1.1, as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD\]. |
| Objective Response Rate (ORR) | Up to approximately 116 weeks | ORR was defined as the percentage of participants who have best response of Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). |
| Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day 1: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 1 Day 22: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 2 Day 1: predose. Cycle = 28 days. | AUC0-24hrs was defined as area under the concentration-time curve from time 0 to 24 hours after dose administration. This study was terminated because of business reasons. Due to study termination, pharmacokinetic (PK) testing was prioritized for dosing arms and timepoints that would provide the required data to support programmatic decision-making and subsequent clinical studies. Zero participants analyzed entered in the table indicate data were not generated and no data were available. AUC0-24 is reported as geometric mean with a percent coefficient of variation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Vevorisertib 5 mg QD Participants received vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity. | 4 |
| Part 1: Vevorisertib 10 mg QD Participants received vevorisertib 10 mg orally QD until discontinuation or toxicity. | 4 |
| Part 1: Vevorisertib 20 mg QD Participants received vevorisertib 20 mg orally QD until discontinuation or toxicity. | 1 |
| Part 1: Vevorisertib 25 mg QD Participants received vevorisertib 25 mg orally QD until discontinuation or toxicity. | 3 |
| Part 1: Vevorisertib 25 mg QOD Participants received vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity. | 3 |
| Part 1: Vevorisertib 50 mg QD Participants received vevorisertib 50 mg orally QD until discontinuation or toxicity. | 3 |
| Part 1: Vevorisertib 75 mg QD Participants received vevorisertib 75 mg orally QD until discontinuation or toxicity. | 33 |
| Part 1: Vevorisertib 100 mg QD Participants received vevorisertib 100 mg orally QD until discontinuation or toxicity. | 8 |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel Participants received vevorisertib 50 mg orally QD plus paclitaxel 80 mg/m\^2 via intravenous (IV) infusion on Days 1, 7, 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. | 5 |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel Participants received vevorisertib 75 mg orally QD plus paclitaxel 80 mg/m\^2 via IV infusion on Days 1, 7, and 15 followed by a week of rest of each 28-day cycle until discontinuation or toxicity. | 5 |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant Participants received vevorisertib 50 mg orally QD plus fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. | 3 |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant Participants received vevorisertib 75 mg orally QD plus fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until discontinuation or toxicity. | 6 |
| Total | 78 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 1 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 2 | 2 | 1 | 0 |
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 0 | 6 | 0 | 0 | 1 | 1 | 4 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Other | 4 | 4 | 1 | 2 | 3 | 3 | 18 | 8 | 0 | 1 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 | 4 | 0 | 2 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1: Vevorisertib 5 mg QD | Part 1: Vevorisertib 10 mg QD | Part 1: Vevorisertib 20 mg QD | Part 1: Vevorisertib 25 mg QD | Part 1: Vevorisertib 25 mg QOD | Part 1: Vevorisertib 50 mg QD | Part 1: Vevorisertib 75 mg QD | Part 1: Vevorisertib 100 mg QD | Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 60.5 Years STANDARD_DEVIATION 11.5 | 57.0 Years STANDARD_DEVIATION 14.4 | 65.0 Years | 62.0 Years STANDARD_DEVIATION 3.6 | 58.3 Years STANDARD_DEVIATION 11.6 | 53.0 Years STANDARD_DEVIATION 20.2 | 58.6 Years STANDARD_DEVIATION 11.9 | 59.0 Years STANDARD_DEVIATION 8.4 | 57.2 Years STANDARD_DEVIATION 19.7 | 59.8 Years STANDARD_DEVIATION 11.3 | 52.3 Years STANDARD_DEVIATION 7.6 | 65.8 Years STANDARD_DEVIATION 5.6 | 59.0 Years STANDARD_DEVIATION 11.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 1 Participants | 3 Participants | 3 Participants | 3 Participants | 31 Participants | 7 Participants | 5 Participants | 5 Participants | 3 Participants | 6 Participants | 74 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 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 |
| 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 | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 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) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 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) 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 | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 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 |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 1 Participants | 3 Participants | 3 Participants | 3 Participants | 30 Participants | 6 Participants | 5 Participants | 4 Participants | 3 Participants | 6 Participants | 71 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 0 Participants | 3 Participants | 3 Participants | 3 Participants | 19 Participants | 7 Participants | 5 Participants | 2 Participants | 3 Participants | 6 Participants | 56 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 14 Participants | 1 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 22 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 | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 4 | 2 / 4 | 0 / 1 | 1 / 3 | 0 / 3 | 1 / 3 | 7 / 33 | 2 / 8 | 2 / 5 | 2 / 5 | 1 / 3 | 0 / 6 |
| other Total, other adverse events | 4 / 4 | 4 / 4 | 1 / 1 | 3 / 3 | 3 / 3 | 3 / 3 | 32 / 32 | 8 / 8 | 5 / 5 | 5 / 5 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 2 / 4 | 3 / 4 | 0 / 1 | 2 / 3 | 1 / 3 | 2 / 3 | 12 / 32 | 5 / 8 | 3 / 5 | 2 / 5 | 0 / 3 | 3 / 6 |
Outcome results
Primary
Number of Participants Who Discontinue Study Treatment Due to an AE
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with study-drug treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Time frame: Up to approximately 116 weeks
Population: All participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Vevorisertib 5 mg QD | Number of Participants Who Discontinue Study Treatment Due to an AE | 0 Participants |
| Part 1: Vevorisertib 10 mg QD | Number of Participants Who Discontinue Study Treatment Due to an AE | 1 Participants |
| Part 1: Vevorisertib 20 mg | Number of Participants Who Discontinue Study Treatment Due to an AE | 0 Participants |
| Part 1: Vevorisertib 25 mg QD | Number of Participants Who Discontinue Study Treatment Due to an AE | 0 Participants |
| Part 1: Vevorisertib 25 mg QOD | Number of Participants Who Discontinue Study Treatment Due to an AE | 0 Participants |
| Part 1: Vevorisertib 50 mg QD | Number of Participants Who Discontinue Study Treatment Due to an AE | 0 Participants |
| Part 1: Vevorisertib 75 mg QD | Number of Participants Who Discontinue Study Treatment Due to an AE | 3 Participants |
| Part 1: Vevorisertib 100 mg QD | Number of Participants Who Discontinue Study Treatment Due to an AE | 0 Participants |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Number of Participants Who Discontinue Study Treatment Due to an AE | 1 Participants |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Number of Participants Who Discontinue Study Treatment Due to an AE | 1 Participants |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Number of Participants Who Discontinue Study Treatment Due to an AE | 0 Participants |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Number of Participants Who Discontinue Study Treatment Due to an AE | 1 Participants |
Primary
Number of Participants Who Experience One or More Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with study-drug treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Time frame: Up to approximately 120 weeks
Population: All participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Vevorisertib 5 mg QD | Number of Participants Who Experience One or More Adverse Events (AEs) | 4 Participants |
| Part 1: Vevorisertib 10 mg QD | Number of Participants Who Experience One or More Adverse Events (AEs) | 4 Participants |
| Part 1: Vevorisertib 20 mg | Number of Participants Who Experience One or More Adverse Events (AEs) | 1 Participants |
| Part 1: Vevorisertib 25 mg QD | Number of Participants Who Experience One or More Adverse Events (AEs) | 3 Participants |
| Part 1: Vevorisertib 25 mg QOD | Number of Participants Who Experience One or More Adverse Events (AEs) | 3 Participants |
| Part 1: Vevorisertib 50 mg QD | Number of Participants Who Experience One or More Adverse Events (AEs) | 3 Participants |
| Part 1: Vevorisertib 75 mg QD | Number of Participants Who Experience One or More Adverse Events (AEs) | 32 Participants |
| Part 1: Vevorisertib 100 mg QD | Number of Participants Who Experience One or More Adverse Events (AEs) | 8 Participants |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Number of Participants Who Experience One or More Adverse Events (AEs) | 5 Participants |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Number of Participants Who Experience One or More Adverse Events (AEs) | 5 Participants |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Number of Participants Who Experience One or More Adverse Events (AEs) | 3 Participants |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Number of Participants Who Experience One or More Adverse Events (AEs) | 6 Participants |
Secondary
Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib
AUC0-24hrs was defined as area under the concentration-time curve from time 0 to 24 hours after dose administration. This study was terminated because of business reasons. Due to study termination, pharmacokinetic (PK) testing was prioritized for dosing arms and timepoints that would provide the required data to support programmatic decision-making and subsequent clinical studies. Zero participants analyzed entered in the table indicate data were not generated and no data were available. AUC0-24 is reported as geometric mean with a percent coefficient of variation.
Time frame: Cycle 1 Day 1: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 1 Day 22: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 2 Day 1: predose. Cycle = 28 days.
Population: All participants who received at least 1 dose of study drug and had ≥1 sample collected to assess AUC0-24 at each time point. Due to termination of the study, PK testing was prioritized for dosing arms and time points that would support programmatic decision-making and subsequent clinical studies. Zero participants analyzed indicate data were not generated and no data were available.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Vevorisertib 5 mg QD | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day1 | NA hours*ng/mL | — |
| Part 1: Vevorisertib 10 mg QD | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day1 | 12.27 hours*ng/mL | — |
| Part 1: Vevorisertib 10 mg QD | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day 22 | 67.89 hours*ng/mL | Geometric Coefficient of Variation 197.1 |
| Part 1: Vevorisertib 20 mg | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day1 | 42.2 hours*ng/mL | — |
| Part 1: Vevorisertib 20 mg | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day 22 | 78.5 hours*ng/mL | — |
| Part 1: Vevorisertib 25 mg QD | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day1 | 244.1 hours*ng/mL | Geometric Coefficient of Variation 113.3 |
| Part 1: Vevorisertib 25 mg QD | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day 22 | 501.8 hours*ng/mL | Geometric Coefficient of Variation 35.5 |
| Part 1: Vevorisertib 25 mg QOD | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day 22 | 181.2 hours*ng/mL | Geometric Coefficient of Variation 59 |
| Part 1: Vevorisertib 25 mg QOD | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day1 | 128.6 hours*ng/mL | Geometric Coefficient of Variation 52.4 |
| Part 1: Vevorisertib 50 mg QD | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day1 | 287.5 hours*ng/mL | Geometric Coefficient of Variation 4.5 |
| Part 1: Vevorisertib 50 mg QD | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day 22 | 543.8 hours*ng/mL | Geometric Coefficient of Variation 78.2 |
| Part 1: Vevorisertib 75 mg QD | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day1 | 667.6 hours*ng/mL | Geometric Coefficient of Variation 84.6 |
| Part 1: Vevorisertib 75 mg QD | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day 22 | 1832 hours*ng/mL | Geometric Coefficient of Variation 68.5 |
| Part 1: Vevorisertib 75 mg QD | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 2 Day 1 | 2013 hours*ng/mL | Geometric Coefficient of Variation 66.4 |
| Part 1: Vevorisertib 100 mg QD | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day 22 | 1786 hours*ng/mL | Geometric Coefficient of Variation 82.4 |
| Part 1: Vevorisertib 100 mg QD | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day1 | 786.1 hours*ng/mL | Geometric Coefficient of Variation 117.7 |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 2 Day 1 | 837.2 hours*ng/mL | Geometric Coefficient of Variation 200.6 |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day1 | 391.1 hours*ng/mL | — |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 2 Day 1 | 1280 hours*ng/mL | Geometric Coefficient of Variation 39.1 |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day1 | 649.6 hours*ng/mL | Geometric Coefficient of Variation 41.7 |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day1 | 449 hours*ng/mL | — |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 2 Day 1 | 750.7 hours*ng/mL | Geometric Coefficient of Variation 67 |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 1 Day1 | 1115 hours*ng/mL | Geometric Coefficient of Variation 73.5 |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib | Cycle 2 Day 1 | 1948 hours*ng/mL | Geometric Coefficient of Variation 49.7 |
Secondary
Best Overall Response (BOR)
BOR was assessed using RECIST 1.1. Response categories included: CR: disappearance of all target lesions; PR: at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD; Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; and Inevaluable: participants who have SD as their best overall response but fail to achieve the protocol-defined duration for SD. Percentage of participants with CR, PR, SD, PD, or inevaluable as a best overall response have been reported.
Time frame: Up to approximately 116 weeks
Population: All participants who received at least 1 dose of study treatment and had BOR data available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Vevorisertib 5 mg QD | Best Overall Response (BOR) | Complete Response (CR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 5 mg QD | Best Overall Response (BOR) | Inevaluable | 0 Percentage of Participants |
| Part 1: Vevorisertib 5 mg QD | Best Overall Response (BOR) | Stable Disease (SD) | 0 Percentage of Participants |
| Part 1: Vevorisertib 5 mg QD | Best Overall Response (BOR) | Progressive Disease (PD) | 100.0 Percentage of Participants |
| Part 1: Vevorisertib 5 mg QD | Best Overall Response (BOR) | Partial Response (PR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 10 mg QD | Best Overall Response (BOR) | Complete Response (CR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 10 mg QD | Best Overall Response (BOR) | Inevaluable | 0 Percentage of Participants |
| Part 1: Vevorisertib 10 mg QD | Best Overall Response (BOR) | Partial Response (PR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 10 mg QD | Best Overall Response (BOR) | Progressive Disease (PD) | 100.0 Percentage of Participants |
| Part 1: Vevorisertib 10 mg QD | Best Overall Response (BOR) | Stable Disease (SD) | 0 Percentage of Participants |
| Part 1: Vevorisertib 20 mg | Best Overall Response (BOR) | Stable Disease (SD) | 100.0 Percentage of Participants |
| Part 1: Vevorisertib 20 mg | Best Overall Response (BOR) | Partial Response (PR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 20 mg | Best Overall Response (BOR) | Progressive Disease (PD) | 0 Percentage of Participants |
| Part 1: Vevorisertib 20 mg | Best Overall Response (BOR) | Inevaluable | 0 Percentage of Participants |
| Part 1: Vevorisertib 20 mg | Best Overall Response (BOR) | Complete Response (CR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 25 mg QD | Best Overall Response (BOR) | Partial Response (PR) | 33.3 Percentage of Participants |
| Part 1: Vevorisertib 25 mg QD | Best Overall Response (BOR) | Complete Response (CR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 25 mg QD | Best Overall Response (BOR) | Inevaluable | 0 Percentage of Participants |
| Part 1: Vevorisertib 25 mg QD | Best Overall Response (BOR) | Progressive Disease (PD) | 0 Percentage of Participants |
| Part 1: Vevorisertib 25 mg QD | Best Overall Response (BOR) | Stable Disease (SD) | 66.7 Percentage of Participants |
| Part 1: Vevorisertib 25 mg QOD | Best Overall Response (BOR) | Stable Disease (SD) | 33.3 Percentage of Participants |
| Part 1: Vevorisertib 25 mg QOD | Best Overall Response (BOR) | Complete Response (CR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 25 mg QOD | Best Overall Response (BOR) | Inevaluable | 0 Percentage of Participants |
| Part 1: Vevorisertib 25 mg QOD | Best Overall Response (BOR) | Progressive Disease (PD) | 66.7 Percentage of Participants |
| Part 1: Vevorisertib 25 mg QOD | Best Overall Response (BOR) | Partial Response (PR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 50 mg QD | Best Overall Response (BOR) | Complete Response (CR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 50 mg QD | Best Overall Response (BOR) | Inevaluable | 0 Percentage of Participants |
| Part 1: Vevorisertib 50 mg QD | Best Overall Response (BOR) | Progressive Disease (PD) | 50.0 Percentage of Participants |
| Part 1: Vevorisertib 50 mg QD | Best Overall Response (BOR) | Stable Disease (SD) | 50.0 Percentage of Participants |
| Part 1: Vevorisertib 50 mg QD | Best Overall Response (BOR) | Partial Response (PR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 75 mg QD | Best Overall Response (BOR) | Stable Disease (SD) | 41.7 Percentage of Participants |
| Part 1: Vevorisertib 75 mg QD | Best Overall Response (BOR) | Complete Response (CR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 75 mg QD | Best Overall Response (BOR) | Partial Response (PR) | 4.2 Percentage of Participants |
| Part 1: Vevorisertib 75 mg QD | Best Overall Response (BOR) | Progressive Disease (PD) | 54.2 Percentage of Participants |
| Part 1: Vevorisertib 75 mg QD | Best Overall Response (BOR) | Inevaluable | 0 Percentage of Participants |
| Part 1: Vevorisertib 100 mg QD | Best Overall Response (BOR) | Stable Disease (SD) | 42.9 Percentage of Participants |
| Part 1: Vevorisertib 100 mg QD | Best Overall Response (BOR) | Partial Response (PR) | 14.3 Percentage of Participants |
| Part 1: Vevorisertib 100 mg QD | Best Overall Response (BOR) | Complete Response (CR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 100 mg QD | Best Overall Response (BOR) | Progressive Disease (PD) | 28.6 Percentage of Participants |
| Part 1: Vevorisertib 100 mg QD | Best Overall Response (BOR) | Inevaluable | 14.3 Percentage of Participants |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Best Overall Response (BOR) | Progressive Disease (PD) | 0 Percentage of Participants |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Best Overall Response (BOR) | Stable Disease (SD) | 25.0 Percentage of Participants |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Best Overall Response (BOR) | Inevaluable | 25.0 Percentage of Participants |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Best Overall Response (BOR) | Partial Response (PR) | 50.0 Percentage of Participants |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Best Overall Response (BOR) | Complete Response (CR) | 0 Percentage of Participants |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Best Overall Response (BOR) | Progressive Disease (PD) | 66.7 Percentage of Participants |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Best Overall Response (BOR) | Inevaluable | 0 Percentage of Participants |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Best Overall Response (BOR) | Stable Disease (SD) | 33.3 Percentage of Participants |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Best Overall Response (BOR) | Partial Response (PR) | 0 Percentage of Participants |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Best Overall Response (BOR) | Complete Response (CR) | 0 Percentage of Participants |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Best Overall Response (BOR) | Complete Response (CR) | 0 Percentage of Participants |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Best Overall Response (BOR) | Partial Response (PR) | 0 Percentage of Participants |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Best Overall Response (BOR) | Inevaluable | 0 Percentage of Participants |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Best Overall Response (BOR) | Stable Disease (SD) | 0 Percentage of Participants |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Best Overall Response (BOR) | Progressive Disease (PD) | 100.0 Percentage of Participants |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Best Overall Response (BOR) | Progressive Disease (PD) | 50.0 Percentage of Participants |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Best Overall Response (BOR) | Partial Response (PR) | 0 Percentage of Participants |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Best Overall Response (BOR) | Stable Disease (SD) | 50.0 Percentage of Participants |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Best Overall Response (BOR) | Complete Response (CR) | 0 Percentage of Participants |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Best Overall Response (BOR) | Inevaluable | 0 Percentage of Participants |
Secondary
Disease Control Rate (DCR)
DCR was defined, per RECIST 1.1, as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD\].
Time frame: Up to approximately 116 weeks
Population: All participants who received at least 1 dose of study treatment and had DCR data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Vevorisertib 5 mg QD | Disease Control Rate (DCR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 10 mg QD | Disease Control Rate (DCR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 20 mg | Disease Control Rate (DCR) | 100.0 Percentage of Participants |
| Part 1: Vevorisertib 25 mg QD | Disease Control Rate (DCR) | 100.0 Percentage of Participants |
| Part 1: Vevorisertib 25 mg QOD | Disease Control Rate (DCR) | 33.3 Percentage of Participants |
| Part 1: Vevorisertib 50 mg QD | Disease Control Rate (DCR) | 50.0 Percentage of Participants |
| Part 1: Vevorisertib 75 mg QD | Disease Control Rate (DCR) | 45.8 Percentage of Participants |
| Part 1: Vevorisertib 100 mg QD | Disease Control Rate (DCR) | 57.1 Percentage of Participants |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Disease Control Rate (DCR) | 75.0 Percentage of Participants |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Disease Control Rate (DCR) | 33.3 Percentage of Participants |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Disease Control Rate (DCR) | 0 Percentage of Participants |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Disease Control Rate (DCR) | 50.0 Percentage of Participants |
Secondary
Elimination Half-life (t½) of Vevorisertib
t1/2 was defined as the terminal elimination half-life of drug. This study was terminated because of business reasons. Due to study termination, pharmacokinetic (PK) testing was prioritized for dosing arms and timepoints that would provide the required data to support programmatic decision-making and subsequent clinical studies. Zero participants analyzed entered in the table indicate data were not generated and no data were available. t1/2 is reported as geometric mean with a percent coefficient of variation.
Time frame: Cycle 1 Day 1: predose, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 1 Day 22: predose, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 2 Day 1: predose. Cycle = 28 days.
Population: All participants who received at least 1 dose of study drug and had ≥1 sample collected to assess t1/2 at each time point. Due to termination of the study, PK testing was prioritized for dosing arms and time points that would support programmatic decision-making and subsequent clinical studies. Zero participants analyzed indicate data were not generated and no data were available.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Vevorisertib 5 mg QD | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 1 | NA hours | — |
| Part 1: Vevorisertib 10 mg QD | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 22 | 10.12 hours | Geometric Coefficient of Variation 87 |
| Part 1: Vevorisertib 20 mg | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 1 | 3.68 hours | — |
| Part 1: Vevorisertib 25 mg QD | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 22 | 39.33 hours | Geometric Coefficient of Variation 48.6 |
| Part 1: Vevorisertib 25 mg QD | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 1 | 15.43 hours | Geometric Coefficient of Variation 104.2 |
| Part 1: Vevorisertib 25 mg QOD | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 22 | 21.25 hours | Geometric Coefficient of Variation 13.8 |
| Part 1: Vevorisertib 25 mg QOD | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 1 | 8.257 hours | Geometric Coefficient of Variation 102.7 |
| Part 1: Vevorisertib 50 mg QD | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 22 | 20.03 hours | Geometric Coefficient of Variation 1.6 |
| Part 1: Vevorisertib 50 mg QD | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 1 | 15.94 hours | Geometric Coefficient of Variation 19.3 |
| Part 1: Vevorisertib 75 mg QD | Elimination Half-life (t½) of Vevorisertib | Cycle 2 Day 1 | 22.93 hours | Geometric Coefficient of Variation 36.8 |
| Part 1: Vevorisertib 75 mg QD | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 1 | 12.39 hours | Geometric Coefficient of Variation 37.7 |
| Part 1: Vevorisertib 75 mg QD | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 22 | 12.94 hours | Geometric Coefficient of Variation 71.8 |
| Part 1: Vevorisertib 100 mg QD | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 22 | 24.59 hours | Geometric Coefficient of Variation 6.9 |
| Part 1: Vevorisertib 100 mg QD | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 1 | 7.437 hours | Geometric Coefficient of Variation 69 |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 1 | 8.920 hours | — |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Elimination Half-life (t½) of Vevorisertib | Cycle 2 Day 1 | 20.89 hours | Geometric Coefficient of Variation 70.9 |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 1 | 8.909 hours | Geometric Coefficient of Variation 16.3 |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 1 | 9.48 hours | — |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Elimination Half-life (t½) of Vevorisertib | Cycle 2 Day 1 | 28.78 hours | Geometric Coefficient of Variation 16.3 |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Elimination Half-life (t½) of Vevorisertib | Cycle 2 Day 1 | 11.46 hours | — |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Elimination Half-life (t½) of Vevorisertib | Cycle 1 Day 1 | 9.176 hours | Geometric Coefficient of Variation 46.7 |
Secondary
Maximum Plasma Concentration (Cmax) of Vevorisertib
Cmax was defined as the maximum plasma drug concentration. This study was terminated because of business reasons. Due to study termination, pharmacokinetic (PK) testing was prioritized for dosing arms and timepoints that would provide the required data to support programmatic decision-making and subsequent clinical studies. Zero participants analyzed entered in the table indicate data were not generated and no data were available. Cmax is reported as geometric mean with a percent coefficient of variation.
Time frame: Cycle 1 Day 1: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 1 Day 22: predose and 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose; Cycle 2 Day 1: predose. Cycle = 28 days.
Population: All participants who received at least 1 dose of study drug and had ≥1 sample collected to assess Cmax at each time point. Due to termination of the study, PK testing was prioritized for dosing arms and time points that would support programmatic decision-making and subsequent clinical studies. Zero participants analyzed indicate data were not generated and no data were available.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Vevorisertib 5 mg QD | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 1 | NA ng/mL | — |
| Part 1: Vevorisertib 5 mg QD | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 22 | 4.154 ng/mL | Geometric Coefficient of Variation 45.3 |
| Part 1: Vevorisertib 10 mg QD | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 22 | 12.82 ng/mL | Geometric Coefficient of Variation 71.1 |
| Part 1: Vevorisertib 10 mg QD | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 1 | 4.820 ng/mL | Geometric Coefficient of Variation 80.1 |
| Part 1: Vevorisertib 20 mg | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 22 | 7.79 ng/mL | — |
| Part 1: Vevorisertib 20 mg | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 1 | 15.3 ng/mL | — |
| Part 1: Vevorisertib 25 mg QD | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 22 | 65.40 ng/mL | Geometric Coefficient of Variation 61.5 |
| Part 1: Vevorisertib 25 mg QD | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 1 | 51.39 ng/mL | Geometric Coefficient of Variation 68.1 |
| Part 1: Vevorisertib 25 mg QOD | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 22 | 19.49 ng/mL | Geometric Coefficient of Variation 96.5 |
| Part 1: Vevorisertib 25 mg QOD | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 1 | 22.73 ng/mL | Geometric Coefficient of Variation 5.9 |
| Part 1: Vevorisertib 50 mg QD | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 22 | 55.15 ng/mL | Geometric Coefficient of Variation 76.7 |
| Part 1: Vevorisertib 50 mg QD | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 1 | 59.79 ng/mL | Geometric Coefficient of Variation 7.6 |
| Part 1: Vevorisertib 75 mg QD | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 2 Day 1 | 186.8 ng/mL | Geometric Coefficient of Variation 47.3 |
| Part 1: Vevorisertib 75 mg QD | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 1 | 98.75 ng/mL | Geometric Coefficient of Variation 88.2 |
| Part 1: Vevorisertib 75 mg QD | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 22 | 225.1 ng/mL | Geometric Coefficient of Variation 80 |
| Part 1: Vevorisertib 100 mg QD | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 22 | 207.7 ng/mL | Geometric Coefficient of Variation 80.6 |
| Part 1: Vevorisertib 100 mg QD | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 1 | 122.6 ng/mL | Geometric Coefficient of Variation 107.1 |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 2 Day 1 | 78.36 ng/mL | Geometric Coefficient of Variation 216.8 |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 1 | 29.13 ng/mL | Geometric Coefficient of Variation 245.6 |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 1 | 49.11 ng/mL | Geometric Coefficient of Variation 67 |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 2 Day 1 | 79.52 ng/mL | Geometric Coefficient of Variation 69.6 |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 1 | 91.7 ng/mL | — |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 2 Day 1 | 62.59 ng/mL | Geometric Coefficient of Variation 140.1 |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 2 Day 1 | 138.2 ng/mL | Geometric Coefficient of Variation 48.4 |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Maximum Plasma Concentration (Cmax) of Vevorisertib | Cycle 1 Day 1 | 166.7 ng/mL | Geometric Coefficient of Variation 101.7 |
Secondary
Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)
DLTs consisted of hematologic or non-hematologic toxicities. Hematologic DLT was any grade (Gr) 4 anemia, Gr 4 neutropenia, Gr 4 thrombocytopenia, Gr 3 lasting \>7 days, Gr 3 thrombocytopenia in the presence of bleeding, or ≥ Gr 3 hyperglycemia. Non-hematologic DLT was any Gr 3, 4 or 5 non-hematologic toxicity with the exception of: (1) Gr 3 nausea, vomiting, diarrhea or responding to optimal medical management within 48 hours; (2) alopecia. Per protocol DLTs were analyzed in the first 28-day treatment cycle. The number of participants experiencing DLTs is reported here for all participants who got ≥1 dose of study drug.
Time frame: Cycle 1 (Up to approximately 28 days)
Population: All participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Vevorisertib 5 mg QD | Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | 0 Participants |
| Part 1: Vevorisertib 10 mg QD | Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | 0 Participants |
| Part 1: Vevorisertib 20 mg | Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | 0 Participants |
| Part 1: Vevorisertib 25 mg QD | Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | 0 Participants |
| Part 1: Vevorisertib 25 mg QOD | Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | 0 Participants |
| Part 1: Vevorisertib 50 mg QD | Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | 0 Participants |
| Part 1: Vevorisertib 75 mg QD | Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | 1 Participants |
| Part 1: Vevorisertib 100 mg QD | Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | 1 Participants |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | 0 Participants |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | 1 Participants |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | 0 Participants |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | 0 Participants |
Secondary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants who have best response of Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
Time frame: Up to approximately 116 weeks
Population: All participants who received at least 1 dose of study treatment and had ORR data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Vevorisertib 5 mg QD | Objective Response Rate (ORR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 10 mg QD | Objective Response Rate (ORR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 20 mg | Objective Response Rate (ORR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 25 mg QD | Objective Response Rate (ORR) | 33.3 Percentage of Participants |
| Part 1: Vevorisertib 25 mg QOD | Objective Response Rate (ORR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 50 mg QD | Objective Response Rate (ORR) | 0 Percentage of Participants |
| Part 1: Vevorisertib 75 mg QD | Objective Response Rate (ORR) | 4.2 Percentage of Participants |
| Part 1: Vevorisertib 100 mg QD | Objective Response Rate (ORR) | 14.3 Percentage of Participants |
| Part 2: Vevorisertib 50 mg QD Plus Paclitaxel | Objective Response Rate (ORR) | 50.0 Percentage of Participants |
| Part 2: Vevorisertib 75 mg QD Plus Paclitaxel | Objective Response Rate (ORR) | 0 Percentage of Participants |
| Part 2: Vevorisertib 50 mg QD Plus Fulvestrant | Objective Response Rate (ORR) | 0 Percentage of Participants |
| Part 2: Vevorisertib 75 mg QD Plus Fulvestrant | Objective Response Rate (ORR) | 0 Percentage of Participants |