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)

NCT02761694 | Terminated Phase 1 Results

• 3 other identifiers: 4440-001ARQ 751-101MK-4440-001
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 6

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.

Conditions

Cancer; Solid Tumors

Keywords

AKT1; AKT2; AKT3; PI3K; solid tumors; cancer; ARQ 751; PTEN

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (7)

• 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.

• 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.

• 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.

• 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)

• Objective Response Rate (ORR)

  Up to approximately 116 weeks

Study Arms (12)

Part 1: Vevorisertib 5 mg QD

EXPERIMENTAL

Participants will receive vevorisertib 5 mg orally once a day (QD) until discontinuation or toxicity.

Drug: Vevorisertib

Part 1: Vevorisertib 10 mg QD

EXPERIMENTAL

Participants will receive vevorisertib 10 mg orally QD until discontinuation or toxicity.

Drug: Vevorisertib

Part 1: Vevorisertib 20 mg QD

EXPERIMENTAL

Participants will receive vevorisertib 20 mg orally QD until discontinuation or toxicity.

Drug: Vevorisertib

Part 1: Vevorisertib 25 mg QD

EXPERIMENTAL

Participants will receive vevorisertib 25 mg orally QD until discontinuation or toxicity.

Drug: Vevorisertib

Part 1: Vevorisertib 25 mg QOD

EXPERIMENTAL

Participants will receive vevorisertib 25 mg orally every other day (QOD) until discontinuation or toxicity.

Drug: Vevorisertib

Part 1: Vevorisertib 50 mg QD

EXPERIMENTAL

Participants will receive vevorisertib 50 mg orally QD until discontinuation or toxicity.

Drug: Vevorisertib

Part 1: Vevorisertib 75 mg QD

EXPERIMENTAL

Participants will receive vevorisertib 75 mg orally QD until discontinuation or toxicity.

Drug: Vevorisertib

Part 1: Vevorisertib 100 mg QD

EXPERIMENTAL

Participants will receive vevorisertib 100 mg orally QD until discontinuation or toxicity.

Drug: Vevorisertib

Part 2: Vevorisertib 50 mg QD plus Paclitaxel

EXPERIMENTAL

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; Drug: Paclitaxel

Part 2: Vevorisertib 75 mg QD plus Paclitaxel

EXPERIMENTAL

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; Drug: Paclitaxel

Part 2: Vevorisertib 50 mg QD plus Fulvestrant

EXPERIMENTAL

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; Drug: Fulvestrant

Part 2: Vevorisertib 75 mg QD plus Fulvestrant

EXPERIMENTAL

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; Drug: Fulvestrant

Interventions

Vevorisertib DRUG

Administered as an oral dose every day or every other day.

Also known as: ARQ 751, MK-4440

Part 1: Vevorisertib 10 mg QD; Part 1: Vevorisertib 100 mg QD; Part 1: Vevorisertib 20 mg QD; Part 1: Vevorisertib 25 mg QD; Part 1: Vevorisertib 25 mg QOD; Part 1: Vevorisertib 5 mg QD; Part 1: Vevorisertib 50 mg QD; Part 1: Vevorisertib 75 mg QD; Part 2: Vevorisertib 50 mg QD plus Fulvestrant; Part 2: Vevorisertib 50 mg QD plus Paclitaxel; Part 2: Vevorisertib 75 mg QD plus Fulvestrant; Part 2: Vevorisertib 75 mg QD plus Paclitaxel

Fulvestrant DRUG

Administered as an intramuscular (IM) injection.

Also known as: Faslodex

Part 2: Vevorisertib 50 mg QD plus Fulvestrant; Part 2: Vevorisertib 75 mg QD plus Fulvestrant

Paclitaxel DRUG

Administered as an intravenous (IV) infusion.

Also known as: Taxol

Part 2: Vevorisertib 50 mg QD plus Paclitaxel; Part 2: Vevorisertib 75 mg QD plus Paclitaxel

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed written informed consent granted prior to initiation of any study-specific procedures
• 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

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)

Sponsors & Collaborators

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

Study Sites (6)

Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, 89169, United States

Location

Stephenson Cancer Center

Oklahoma City, Oklahoma, 73104, United States

Location

Charleston Hematology Oncology

Charleston, South Carolina, 29414, United States

Location

The Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Mary Crowley Cancer Research

Dallas, Texas, 75230, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Pant S, Hamilton E, Ulahannan SV, Strauss JF, Braiteh FS, Huang M, Liaw DCH. Phase 1b study of pan-AKT inhibitor vevorisertib alone or with paclitaxel or fulvestrant in PIK3CA/AKT/PTEN-mutated advanced solid tumors. Cancer. 2023 Jun 15;129(12):1919-1929. doi: 10.1002/cncr.34733. Epub 2023 Mar 27.

  PMID: 36970876 RESULT

MeSH Terms

Conditions

Neoplasms

Interventions

Fulvestrant; Paclitaxel

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 29, 2016
• First Posted: May 4, 2016
• Study Start: June 26, 2016
• Primary Completion: March 10, 2021
• Study Completion: March 10, 2021
• Last Updated: May 6, 2023
• Results First Posted: June 15, 2022

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will share

Locations

US (6)