Antineoplastic Agents

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Paclitaxel

Fulvestrant

Albumin-Bound Paclitaxel

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Estrogen Antagonists

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Hormones

Hormone Antagonists

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

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

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

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

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

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

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

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

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.

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.

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.

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.

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

Vevorisertib

Administered as an intramuscular (IM) injection.

Administered as an intravenous (IV) infusion.

Medical Director

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.

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

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)

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

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

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.

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.

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.

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.

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.

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).

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.

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 \[PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD\].

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

The analysis population for All-Cause Mortality included all randomized participants.The analysis population for AEs included all randomized participants who received at least 1 dose of study treatment.

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

Part 1: Vevorisertib 5 mg QD

Participants received vevorisertib 10 mg orally QD until discontinuation or toxicity.

Part 1: Vevorisertib 10 mg QD

Participants received vevorisertib 20 mg orally QD until discontinuation or toxicity.

Part 1: Vevorisertib 20 mg QD

Participants received vevorisertib 25 mg orally QD until discontinuation or toxicity.

Part 1: Vevorisertib 25 mg QD

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

Part 1: Vevorisertib 25 mg QOD

Participants received vevorisertib 50 mg orally QD until discontinuation or toxicity.

Part 1: Vevorisertib 50 mg QD

Participants received vevorisertib 75 mg orally QD until discontinuation or toxicity.

Part 1: Vevorisertib 75 mg QD

Participants received vevorisertib 100 mg orally QD until discontinuation or toxicity.

Part 1: Vevorisertib 100 mg QD

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.

Part 2: Vevorisertib 50 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.

Part 2: Vevorisertib 75 mg QD Plus Paclitaxel

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.

Part 2: Vevorisertib 50 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.

Part 2: Vevorisertib 75 mg QD Plus Fulvestrant

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Senior Vice President, Global Clinical Development

Part 1: Vevorisertib 20 mg

All participants who received at least 1 dose of study treatment.

Number of Participants Who Experience One or More Adverse Events (AEs)

Number of Participants Who Discontinue Study Treatment Due to an AE

Cycle 1 Day 1

Cycle 1 Day 22

Cycle 2 Day 1

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.

Maximum Plasma Concentration (Cmax) of Vevorisertib

Cycle 1 Day1

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.

Area Under the Curve From 0-24 Hours (AUC0-24 Hours) of Vevorisertib

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.

Elimination Half-life (t½) of Vevorisertib

Number of Participants With a Dose-Limiting Toxicity (DLT), for the Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)

All participants who received at least 1 dose of study treatment and had ORR data available.

Objective Response Rate (ORR)

Complete Response (CR)

Partial Response (PR)

Stable Disease (SD)

Progressive Disease (PD)

Inevaluable

All participants who received at least 1 dose of study treatment and had BOR data available.

Best Overall Response (BOR)

All participants who received at least 1 dose of study treatment and had DCR data available.

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