Neoplasms

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Digestive System Diseases

Gland and Hormone Related Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Pancreatic Neoplasms

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Carcinoma, Endometrioid

Endocrine System Diseases

Ovarian Diseases

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Genital Diseases, Female

Genital Diseases

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Female Urogenital Diseases

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Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

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Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Endometrial Neoplasms

Uterine Neoplasms

Pancreatic Cancer

Ovarian Cancer

Ovarian Epithelial Cancer

Natriuretic Agents

All Drugs and Chemicals

Mannitol

Escalating doses of VS-6766 (RO5126766) and Defactinib (VS-6063) were evaluated in patients with advanced solid tumours to establish the recommended phase II dose. Dose escalation followed a 3+3 design with a maximum of four patient cohorts.

This arm is now complete.

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with KRAS mutant NSCLC (20 patients).

This arm is now complete.

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients advanced RAS mutant solid tumours with biopsiable disease (6 patients).

This arm is now complete.

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with LGSOC (20 patients).

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with CRC (10 patients).

This arm is now complete.

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with KRAS G12V mutant NSCLC (10 patients).

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with RAS/RAF mutant endometrioid subtype of gynaecological cancers (ovarian, endometrial, endometriosis-related) (10 patients).

The dose expansion phase will evaluate the recommended phase II dose of the combination of VS-6766 (RO5126766) and Defactinib (VS-6063), as decided in the dose escalation phase in patients with pancreatic cancer (10 patients).

VS-6766 will be supplied as 0.8mg hypromellose (HPMC) capsules for oral administration. The capsule fill consists of VS-6766 and the inactive ingredients mannitol and magnesium stearate.

VS-6766 will be administered on a twice weekly (Monday and Thursday or Tuesday and Friday) schedule for 3 weeks followed by 1 week off in every 4 week cycle, under fasting conditions (approximately 1 hour prior or 2 hours after a meal). The starting dose, based on the previous Phase I trial will be 3.2 mg given orally as a single daily dose. This can be escalated to a maximum of 4mg (as per dose escalation rules in the protocol).

VS-6766

Defactinib is formulated as a white to off-white oval tablet for oral administration and supplied in single unit dose strength of 200 mg in 120 cc (HDPE) bottles. In addition to Defactinib, formulation components include microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, and magnesium stearate.

Patients will receive Defactinib orally immediately after a meal twice daily (approximately every 12 hours) for 3 weeks followed by 1 week off in every 4 week cycle. The starting dose will be 200mg. This can be escalated to a maximum of 400mg (as per dose escalation rules in the protocol).

Defactinib

Udai Banerji, FRCP, PhD

This is a multi-centre, investigator-initiated, dose escalation, Phase I trial of the combination of the FAK inhibitor, Defactinib (VS-6063), and the dual RAF/MEK inhibitor, VS-6766 (RO5126766) in patients with advanced solid tumours. VS-6766 (RO5126766) is the same compound as CH5126766.

There are two parts to this study, the dose escalation phase and the dose expansion phase. In the dose escalation phase, cohorts of 3 to 6 patients will be enrolled to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). This will be followed by a dose expansion phase to further characterise the safety and tolerability and to assess the pharmacodynamic activity of the combination.

This is a multi-centre, investigator-initiated, dose escalation, Phase I trial of the combination of the FAK inhibitor, Defactinib, and the dual RAF/MEK inhibitor, VS-6766 in patients with advanced solid tumours.

There are two parts to this study, the dose escalation phase and the dose expansion phase. In the dose escalation phase, cohorts of 3 to 6 patients were enrolled to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). Up to 24 patients with solid tumours were treated in the dose escalation phase of this study.

The dose escalation phase is now closed to recruitment.

This will be followed by a dose expansion phase of 86 patients to further characterise the safety and tolerability and to assess the pharmacodynamic activity of the combination.

The dose expansion phase is made up of 7 cohorts:

* 20 patients with KRAS mutant non-small-cell lung cancer (NSCLC);
* 7 patients with solid tumours (enriched for those with RAS mutations) willing to undergo biopsies at three time points throughout the study;
* 20 patients with low grade serous ovarian cancer (LGSOC);
* 10 patients with colorectal cancer (CRC);
* 10 patients with KRAS G12V mutant NSCLC;
* 10 patients with RAS/RAF mutant endometrioid subtype of gynaecological cancers (ovarian, endometrial, endometriosis related) and
* 10 patients with pancreatic cancer.

The following cohorts are still open to recruitment:

* Patients with low grade serous ovarian cancer (LGSOC);
* Patients with KRAS G12V mutant NSCLC;
* Patients with RAS/RAF mutant endometrioid subtype of gynaecological cancers (ovarian, endometrial, endometriosis-related) and
* Patients with pancreatic cancer.

Patients will take the two investigational medicinal products (IMPs) as follows:

VS-6766 will be administered orally twice a week on Monday/Thursday or Tuesday/Friday at least one hour prior or two hours after a meal. The starting dose of VS-6766 will be 3.2mg once a day, twice a week and can be escalated to a maximum of 4mg once a day, twice a week.

Defactinib will be administered orally twice a day immediately after a meal. The starting dose of Defactinib will be 200mg twice daily and can be escalated to a maximum of 400mg twice daily.

A cycle length is 4 weeks (28 days). Combination dosing (VS-6766 and Defactinib) will commence on Cycle 1 Day 1 for 3 weeks followed by one week without either drug in week 4 (i.e. 3 weeks on, 1 week off).

For patients consenting to optional biopsies, a run-in dose of VS-6766 will be administered on a single day anywhere between Days -7 to Day -3 in order to facilitate pharmacodynamic (PD) biomarker analysis. Therefore, for patients undergoing biopsies the first cycle will be 5 weeks long and subsequent cycles will consist of 4 weeks.

If this schedule is not tolerated, alternative schedules may be explored following discussion by the Safety Review Committee.

The dose escalation phase will enrol patients with advanced RAS mutant solid tumours.

In the dose expansion phase, patients are assigned to one of the following cohorts based on their diagnosis:

* KRAS mutant NSCLC cohort
* LGSOC cohort
* RAS mutant CRC cohort
* Advanced RAS mutant solid tumour cohort - patients in this cohort must have biopsiable disease, be willing and consent to undergo biopsies at three time-points.
* KRAS G12V mutant NSCLC cohort
* RAS/RAF mutant endometrioid cohort
* Pancreatic cohort

Non-randomised: Participants are expressly assigned by phase of study and diagnosis.

Phase I Trial of Defactinib and VS-6766.

FRAME: A Phase I Trial of the Combination of Defactinib (VS-6063) (FAK Inhibitor) and VS-6766 (RO5126766) (CH5126776) (a Dual RAF/MEK Inhibitor) in Patients With Advanced Solid Tumours

Determination of disease response by RECIST criteria version 1.1 and collection of data related to progression free survival.

Quantification of biomarkers such as p-MEK, p-ERK and p-FAK, E-cadherin and vimentin and enumeration of T cell populations which express CD8, CD4 and CD25.

Correlation of antitumour activity of the combination of VS-6766 and Defactinib with the detection of putative predictive biomarkers of response and resistance in archival tumours and plasma DNA.

To determine the maximum dose at which no more than 1 of 6 patients at the same dose level experience a drug related toxicity (DLT) as specified in the protocol.

To assess the safety and toxicity profile of VS-6766 and Defactinib. To determine causality and grading severity of each adverse event by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Determination of the PK parameter Cmax of VS-6766 and Defactinib when dosed together.

Determination of the PK parameter terminal half-life of VS-6766 and Defactinib when dosed together.

Determination of the PK parameter area under the curve of VS-6766 and Defactinib when dosed together.

Verastem, Inc.

Institute of Cancer Research, United Kingdom

Symptoms and General Pathology

Recurrence

Endocrine Gland Neoplasms

Antineoplastic Agents

Anti-Infective Agents

Paclitaxel

Doxorubicin

Liposomal doxorubicin

Letrozole

Albumin-Bound Paclitaxel

Topotecan

Anastrozole

Tubulin Modulators

Antimitotic Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Aromatase Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Topoisomerase I Inhibitors

Antineoplastic Agents, Hormonal

Avutometinib 3.2 mg, PO, twice weekly (eg, Monday/Thursday, Tuesday/Friday, or Wednesday/Saturday) for 21 days on, 7 days off in a 28-day (4 weeks) cycle in combination with defactinib 200 mg, PO, twice daily for 21 days on, 7 days off in a 28-day(4 week) cycle.

Patients will receive one of the following therapies as determined by the Investigator:

* Pegylated liposomal doxorubicin: 40 mg/m2 IV on Day 1 of each 28-day (4 week) cycle.
* Paclitaxel: 80 mg/m2 IV on Days 1, 8, and 15 of each 28-day (4 week) cycle.
* Topotecan: 4 mg/m2 IV on Days 1, 8, and 15 of each 28-day (4 week) cycle.
* Anastrozole: 1 mg, PO, once daily of each 28-day (4 week) cycle.
* Letrozole: 2.5 mg, PO, once daily of each 28-day (4 week) cycle.

avutometinib

Pegylated liposomal doxorubicin

Verastem Call Center

Kelly Fillbrant

Lyndsay Willmott, MD

Surya Nagesh

Ritu Salani, MD

Lisa Baker

Alessandro Santin, MD

Karla Hernandez-Cruz

Robert Holloway, MD

Mary Jo Luser

Bradley Monk, MD

Michele Britto

Mary Tilley Jenkins-Vogel, MD

Elizabeth Linnik

Robert Morris, MD

Kayla McDonald

Lauren Bollinger, MD

Linda Odibo

Premal Thaker, MD

Rachel Grisham

Rachel Grisham, MD

Jacqueline Ludwig

Peter Rose, MD

Stephanie Chaney

Christina Washington, MD

Jeanne Scahffer

Charles Anderson, MD

Jennifer Thompson

Erin Salinas, MD

Siobhan Guyach

Thomas Krivak, MD

Michelle Owens

Lynn Knowles, MD

Nori Sullivan

Noelle Cloven, MD

Shannon Syring

Antonio Santillan Gomez, MD

Christina Genthon

Sandra Thornton

Christine Lee, MD

Shelly Maxfield

Anna M Priebe, MD

Magnifique Irakoze

Kari Ring, MD

Monica Cochrane

Robert Marsh, MD

Amy Morrow

Jeffrey Goh, MD

Vineet Kwatra, MD

Meena Okera, MD

Christian Paul Medina

Shibani Nicum, MD

Rowan Miller, MD

Kylie Fitch

Susana Banerjee, MD

Susana Banerjee, MBBS, MA, PhD

MD Verastem

This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with defactinib versus Investigator's choice of treatments (ICT) in subjects with recurrent LGSOC who have progressed on a prior platinum-based therapy.

This international, randomized, open-label, Phase 3 study will compare the investigational combination of avutometinib plus defactinib versus Investigator's Choice of Treatments (ICT) in patients with recurrent LGSOC who have progressed on a prior platinum-based therapy. Avutometinib and defactinib are both a type of drug called a kinase inhibitor. Kinase inhibitors block cancer cell growth. The study will compare the progression-free survival (PFS) of the combination of avutometinib plus defactinib versus ICT. The study will also evaluate the effect of the combination on safety, overall survival, other efficacy endpoints, and health-related quality of life and disease related symptoms. The study is being conducted by gynecological cancer specialists. Patients who are eligible and agree to participate in this study will be treated with either a combination of avutometinib with defactinib, or with one of five standard of care NCCN and ESMO treatment recommendations for recurrent LGSOC, and then with subsequent follow up appointments. Patients who originally received one of the standard of care treatments who are determined to have progressive disease may be eligible to crossover to receive the investigational combination avutometinib plus defactinib.Avutometinib and defactinib are investigational drugs that have not been approved by the U.S. Food and Drug Administration (FDA)

A Study of Avutometinib (VS-6766) + Defactinib (VS-6063) in Recurrent Low-Grade Serous Ovarian Cancer

A Phase 3, Randomized, Open-Label Study of Combination Therapy With Avutometinib Plus Defactinib Versus Investigator's Choice of Treatment in Patients With Recurrent Low-Grade Serous Ovarian Cancer (LGSOC) (RAMP 301)

Confirmed overall response rate per RECIST 1.1 per blinded independent central review (BICR)

From the time of first dose of study intervention to PD as assessed per RECIST 1.1 or death from any cause

From the time of first dose of study intervention to PD as assessed per RECIST 1.1 by Investigator or death from any cause

Count of AE and SAEs by grade, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading scale

Area under plasma Concentration (AUC) 0 to t

The EORTC QLQ-C30 is a questionnaire to assess quality of life of ovarian cancer patients. It is composed of 30 questions. An overall scoring range is from 0 to 100. A high scales score represents a higher response level. Thus, a high score for a functional scale represents a high/healthy level of function, a high score for the global health status/QOL represents a high QOL, but a high score for a symptom scale/item represents a high level of symptomatology/problems. Quality of life measured by EORTC QLQ-C30. These are validated questionnaires to be answered by patients.

The EORTC QLQ-OV28 is a questionnaire to assess quality of life of ovarian cancer patients. It is composed of 28 questions. An overall scoring range is from 0 to 100. A high scales score represents a higher response level. Thus, a high score for a functional scale represents a high/healthy level of function, a high score for the global health status/QOL represents a high QOL, but a high score for a symptom scale/item represents a high level of symptomatology/problems.

GOG Foundation

European Network of Gynaecological Oncological Trial Groups (ENGOT)

Cystadenocarcinoma, Serous

Cystadenocarcinoma

Neoplasms, Cystic, Mucinous, and Serous

Adenocarcinoma of the Appendix

To determine the optimal regimen, either avutometinib(VS-6766) monotherapy or avutometinib (VS-6766) in combination with defactinib, for subsequent evaluation for efficacy in the Expansion Phase (Part B)

To determine the efficacy of the optimal regimen identified from Part A

To evaluate additional efficacy parameters for the optimal regimen identified in Part A.

To evaluate additional efficacy parameters for a lower dose of avutometinib in combination with defactinib

avutometinib (VS-6766)

avutometinib (VS-6766) and defactinib combination

avutometinib (VS-6766) and defactinib

Susana Banerjee, MBBS,MA,PhD

This study will assess the safety and efficacy of avutometinib (VS-6766) monotherapy and in combination with defactinib in subjects with recurrent Low-Grade Serous Ovarian Cancer (LGSOC)

This is a multicenter, randomized, open-label Phase 2 study designed to evaluate safety and tolerability and preliminary efficacy of avutometinib (VS-6766) versus avutometinib (VS-6766) in combination with defactinib in subjects with molecularly profiled recurrent LGSOC.

A Study of Avutometinib (VS-6766) v. Avutometinib (VS-6766) + Defactinib in Recurrent Low-Grade Serous Ovarian Cancer With and Without a KRAS Mutation

A Phase 2 Study of Avutometinib (VS-6766) (Dual RAF/MEK Inhibitor) Alone and In Combination With Defactinib (FAK Inhibitor) in Recurrent Low-Grade Serous Ovarian Cancer (LGSOC)

Confirmed overall response rate per RECIST 1.1

Confirmed ORR defined according to RECIST 1.1

Proportioned subjects achieving a CR or PR as assess by the investigator

From time of first response to PD as assessed by the BIRC

From time of first dose of study intervention to PD or death for any cause

From time of first dose of study intervention to death

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase I Trial of Defactinib and VS-6766.	NCT03875820	NSCLC Low Grade Serou... Endometrioid Ca... Pancreatic Canc...	VS-6766 Defactinib	18 Years -	Institute of Cancer Research, United Kingdom
A Study of Avutometinib (VS-6766) + Defactinib (VS-6063) in Recurrent Low-Grade Serous Ovarian Cancer	NCT06072781	Low Grade Serou...	avutometinib Defactinib Pegylated lipos... Paclitaxel Topotecan Letrozole Anastrozole	18 Years -	Verastem, Inc.
A Study of Avutometinib (VS-6766) v. Avutometinib (VS-6766) + Defactinib in Recurrent Low-Grade Serous Ovarian Cancer With and Without a KRAS Mutation	NCT04625270	Low Grade Ovari... Ovarian Cancer	avutometinib (V... avutometinib (V...	18 Years -	Verastem, Inc.

Spots Global Cancer Trial Database for low grade serous ovarian cancer