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)

Stopped early · Phase 1

Conditions studied: Cancer, Solid Tumors

In brief

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.

Key facts

Study ID

NCT02761694

Run by

ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)

People needed

78

Starts

2016-06-26

Expected to finish

2021-03-10

Last updated by the study team

2023-05-06

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• 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

You may not qualify if…

• 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)

Where it is running

• Comprehensive Cancer Centers of Nevada — Las Vegas, Nevada, United States
• Stephenson Cancer Center — Oklahoma City, Oklahoma, United States
• Charleston Hematology Oncology — Charleston, South Carolina, United States
• The Sarah Cannon Research Institute — Nashville, Tennessee, United States
• Mary Crowley Cancer Research — Dallas, Texas, United States
• MD Anderson Cancer Center — Houston, Texas, United States

Full record on ClinicalTrials.gov

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