Vevorisertib (ARQ 751) as a Single Agent or in Combination With Other Anti-Cancer Agents, in Solid Tumors With PIK3CA / AKT / PTEN Mutations (MK-4440-001)

Study Overview
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Brief Summary
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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
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This study was terminated due to business reasons, and pharmacokinetic (PK) testing was prioritized.

Official Title
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A Phase 1b Study of ARQ 751 as a Single Agent or in Combination With Other Anti-cancer Agents in Adult Subjects With Advanced Solid Tumors With PIK3CA / AKT / PTEN Mutations

Conditions
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Cancer, Solid Tumors

Intervention / Treatment
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* Drug: Vevorisertib
* Drug: Fulvestrant
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Signed written informed consent granted prior to initiation of any study-specific procedures 18 years of age and older 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) 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 For combination arms; participants should be eligible for paclitaxel or fulvestrant therapy as per Investigator assessment 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 Has at least one measurable target lesion according to RECIST v. 1.1 Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1 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): 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 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 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 Metabolic Glycated hemoglobin (HbA1c) ≤ 8% (≤ 64 mmol/mol) 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 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 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 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 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 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. Unable or unwilling to swallow the complete daily dose of vevorisertib 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) 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 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 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) 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 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) A heart rate corrected QT (QTc) interval ≥ 480 msec, using the Fridericia's formula QTcF 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 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 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 Blood transfusion or administration of growth factors within 5 days prior to a blood draw being used to confirm eligibility Pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Vevorisertib 5 mg QD<br>Participants will receive vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity. | Drug: Vevorisertib<br>* Administered as an oral dose every day or every other day.<br>* Other names: MK-4440;|
| Experimental: Part 1: Vevorisertib 10 mg QD<br>Participants will receive vevorisertib 10 mg orally QD until discontinuation or toxicity. | Drug: Vevorisertib<br>* Administered as an oral dose every day or every other day.<br>* Other names: MK-4440;|
| Experimental: Part 1: Vevorisertib 20 mg QD<br>Participants will receive vevorisertib 20 mg orally QD until discontinuation or toxicity. | Drug: Vevorisertib<br>* Administered as an oral dose every day or every other day.<br>* Other names: MK-4440;|
| Experimental: Part 1: Vevorisertib 25 mg QD<br>Participants will receive vevorisertib 25 mg orally QD until discontinuation or toxicity. | Drug: Vevorisertib<br>* Administered as an oral dose every day or every other day.<br>* Other names: MK-4440;|
| Experimental: Part 1: Vevorisertib 25 mg QOD<br>Participants will receive vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity. | Drug: Vevorisertib<br>* Administered as an oral dose every day or every other day.<br>* Other names: MK-4440;|
| Experimental: Part 1: Vevorisertib 50 mg QD<br>Participants will receive vevorisertib 50 mg orally QD until discontinuation or toxicity. | Drug: Vevorisertib<br>* Administered as an oral dose every day or every other day.<br>* Other names: MK-4440;|
| Experimental: Part 1: Vevorisertib 75 mg QD<br>Participants will receive vevorisertib 75 mg orally QD until discontinuation or toxicity. | Drug: Vevorisertib<br>* Administered as an oral dose every day or every other day.<br>* Other names: MK-4440;|
| Experimental: Part 1: Vevorisertib 100 mg QD<br>Participants will receive vevorisertib 100 mg orally QD until discontinuation or toxicity. | Drug: Vevorisertib<br>* Administered as an oral dose every day or every other day.<br>* Other names: MK-4440;|
| Experimental: Part 2: Vevorisertib 50 mg QD plus Paclitaxel<br>Participants will receive 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. | Drug: Vevorisertib<br>* Administered as an oral dose every day or every other day.<br>* Other names: MK-4440;Drug: Paclitaxel<br>* Administered as an intravenous (IV) infusion.<br>* Other names: Taxol;|
| Experimental: Part 2: Vevorisertib 75 mg QD plus Paclitaxel<br>Participants will receive 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. | Drug: Vevorisertib<br>* Administered as an oral dose every day or every other day.<br>* Other names: MK-4440;Drug: Paclitaxel<br>* Administered as an intravenous (IV) infusion.<br>* Other names: Taxol;|
| Experimental: Part 2: Vevorisertib 50 mg QD plus Fulvestrant<br>Participants will receive 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. | Drug: Vevorisertib<br>* Administered as an oral dose every day or every other day.<br>* Other names: MK-4440;Drug: Fulvestrant<br>* Administered as an intramuscular (IM) injection.<br>* Other names: Faslodex;|
| Experimental: Part 2: Vevorisertib 75 mg QD plus Fulvestrant<br>Participants will receive 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. | Drug: Vevorisertib<br>* Administered as an oral dose every day or every other day.<br>* Other names: MK-4440;Drug: Fulvestrant<br>* Administered as an intramuscular (IM) injection.<br>* Other names: Faslodex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to approximately 120 weeks | 
| 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. | Up to approximately 116 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | Cycle 1 (Up to approximately 28 days) | 
| 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). | Up to approximately 116 weeks | 
| 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. | Up to approximately 116 weeks | 
| 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]. | Up to approximately 116 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AKT1, AKT2, AKT3, PI3K, solid tumors, cancer, ARQ 751, PTEN