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MRTX1719 RP2D administered to separate cohorts of patients with selected solid tumor malignancies with MTAP homozygous deletion to include the following: Mesothelioma, Pancreatic Adenocarcinoma, NSCLC, Malignant Peripheral Nerve Sheath Tumor, Other Solid Tumors

MRTX1719

BMS Study Connect Contact Center www.BMSStudyConnect.com

www.BMSStudyConnect.com NCT05245500 14 sites

Mayo Clinic

Research site

Bristol-Myers Squibb, MD

This is a Phase 1/2, open-label, multicenter, study of the safety, tolerability, PK, PD, and anti-tumor activity of MRTX1719 patients with advanced, unresectable or metastatic solid tumor malignancy with homozygous deletion of the MTAP gene.

This first-in-human clinical trial will begin with an exploration of MRTX1719 dose and regimen. As potentially viable regimens are identified, Phase 1b expansion cohorts may be implemented to ensure sufficient safety experience, PK information, compare food effect and relative bioavailability between capsules and tablets, and early evidence of clinical activity are available to recommend Phase 2 regimens. In Phase 2, separate cohorts of patients by histological diagnosis and/or baseline characteristics will be evaluated for the clinical activity and efficacy of MRTX1719.

Phase 1/2 Study of MRTX1719 in Solid Tumors With MTAP Deletion

A Phase 1/2 Multiple Expansion Cohort Trial of MRTX1719 in Patients With Advanced Solid Tumors With Homozygous MTAP Deletion

Mirati Therapeutics Inc.

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Blood and Lymph Conditions

Immune System Diseases

Nutritional and Metabolic Diseases

Prostatic Neoplasms

Carcinoma, Squamous Cell

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Anemia

Lymphoma

Anus Neoplasms

Fanconi Syndrome

Fanconi Anemia

Lymphoma, Non-Hodgkin

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Ovarian Cancer

Ovarian Epithelial Cancer

Lymphosarcoma

Anal Cancer

Congenital Aplastic Anemia

SRA737 will be administered orally on each day of a 28-day cycle. Subjects will receive a single dose of SRA737 between 4 to 7 days prior to starting the first cycle for PK profiling. Subjects can continue taking SRA737 if they are receiving clinical benefit and able to safely take the drug and follow the requirements of the study.

SRA737

The purpose of this clinical study is to establish the safety profile, determine the maximum tolerated dose (MTD) and recommend a Phase 2 dose and schedule of SRA737; and to evaluate the efficacy of SRA737 in prospectively-selected subjects with genetically-defined tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to checkpoint kinase 1 (Chk1) inhibition via synthetic lethality. Specific cancer indications that frequently harbor these genetic mutations will be studied.

SRA737 is a potent, highly selective, orally bioavailable small molecule inhibitor of Chk1, a key regulator of cell cycle progression and the DNA Damage Response (DDR) replication stress response. In cancer cells, intrinsic replication stress (RS) is induced by factors such as oncogenes (e.g., CCNE1 or MYC), genetic mutations in DNA repair machinery (e.g. BRCA1 or FANCA), genetic mutations leading to a dysregulated cell cycle (e.g., TP53 or RAD50) or other genomic alterations. This replication stress results in persistent DNA damage and genomic instability, leading to an increased dependency on Chk1 for survival. Targeted inhibition of Chk1 by SRA737 may therefore be synthetically lethal to cancer cells with elevated intrinsic RS.

This study has been designed to: establish the safety profile; determine the pharmacokinetic profile; identify the optimal dose, schedule, and MTD; obtain preliminary evidence of activity; and evaluate SRA737's efficacy in prospectively-selected subjects with tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to Chk1 inhibition via synthetic lethality.

This clinical study consists of two phases, a Dose Escalation Phase 1 portion and a Cohort Expansion Phase 2 portion.

In the Dose Escalation Phase 1 portion, cohorts consisting initially of a single subject will receive escalating doses of SRA737, administered orally on a continuous daily dosing schedule in 28-day cycles. Once an SRA737-related Grade 2 toxicity is observed in a dose escalation cohort during Cycle 1, that cohort will be expanded to 3 to 6 subjects, and subsequent dose level cohorts will follow a rolling 6 design until the MTD has been identified.

In the Cohort Expansion Phase 2 portion, subjects with genetically-defined tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to Chk1 inhibition will be prospectively enrolled into six indication-specific cohorts to explore the preliminary efficacy of SRA737. Subjects must have advanced or metastatic disease of one of the following types:

* castration-resistant prostate cancer (mCRPC);
* high grade serous ovarian cancer (HGSOC) without CCNE1 gene amplification;
* HGSOC with CCNE1 gene amplification (or alternative genetic alteration with similar functional effect);
* non-small cell lung cancer (NSCLC);
* head and neck squamous cell carcinoma (HNSCC) or squamous cell carcinoma of the anus (SCCA); and
* colorectal cancer (mCRC).

To qualify for enrolment in the Cohort Expansion Phase 2 portion, the subject's tumor must have a confirmed combination of mutations which are expected to confer sensitivity to Chk1 inhibition, determined by the Sponsor's review of genetic abnormalities detected in the following categories:

* Oncogenic drivers such as CCNE1 or MYC, etc.
* Genes involved in the DNA repair process including BRCA1, BRCA2, FANC genes, mismatch repair (MMR) genetic alterations and/or high microsatellite instability.
* Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as TP53, RAD50, etc. For patients with HNSCC or SCCA, positive human papilloma virus (HPV) status is also considered for eligibility.
* Genetic indicators of replicative stress such as gain of function/amplification of CHEK1, ATR or other related genes.

Tumor genetics will be prospectively determined using Next-Generation Sequencing.

A Phase 1/2 Trial of SRA737 in Subjects With Advanced Cancer

A Phase 1/2 Trial of SRA737 (a Chk1 Inhibitor) Administered Orally in Subjects With Advanced Cancer

Treatment-emergent adverse events (TEAEs) were reported until the safety Follow up (SFU) visit, 30 days after the last dose of SRA737 or prior to the initiation of a new anticancer treatment, whichever came first.

The highest dose at which ≤ 33% of subjects have a dose limiting toxicity (DLT) in a cohort of up to 6 subjects.

The RP2D and schedule were defined by the Cohort Review Committee at the end of the study and took all clinically relevant toxicity, PK and PDn data into account. The RP2D was to be a dose equal to or less than the MTD for the selected schedule.

The disease control rate (DCR) was defined as the number of subjects achieving complete response (CR) + partial response (PR) + stable disease (SD) per RECIST 1.1 criteria. Since no subjects achieved CR or PR in this study, the DCR represents the proportion of subjects in each group who achieved SD.

Time to progression (TTP) was defined as the time from Cycle 1 Day 1 to the earliest date of radiographic disease progression per RECIST 1.1, or if the subject did not experience disease progression, to the last imaging assessment. TTP was analyzed using the K-M method.

Progression free survival (PFS) was defined as time from Cycle 1 Day 1 to the earliest date of radiographic disease progression per RECIST 1.1 or death, whichever happened first. Censoring rules are defined in the SAP. PFS was analyzed using the K-M method.

Overall survival (OS) was defined as time from Cycle 1 Day 1 to the date of death (or date last known to be alive). OS was analyzed using the K-M method.

Sierra Oncology LLC - a GSK company

An AE was defined as any untoward, undesired, or unplanned medical occurrence in a subject administered SRA737. All AEs and SAEs were assessed for seriousness, causality, and expectedness.

As specified in the Statistical Analysis Plan, the frequency of each AE was evaluated in the overall Safety Evaluable Population (all enrolled subjects who receive at least 1 dose of SRA737) of patients with advanced solid tumors, irrespective of tumor type. All AEs collected are included in the summary.

Due to the small numbers of patients in some tumor type subgroups and with the intention of displaying the overall safety profile of SRA737 in advanced solid tumors, the frequency of each AE was evaluated in the overall Safety Evaluable Population rather than by tumor type subgroups. The Safety Evaluable Population includes all enrolled subjects who receive at least 1 dose of SRA737.

Safety Evaluable Population

Metastatic colorectal cancer (CRC) defined as histologically and/or cytologically confirmed CRC, and must have received at least 1 prior regimen for advanced/metastatic disease.

Colorectal Cancer

High grade serous ovarian cancer (HGSOC) defined as histologically confirmed high grade serous ovarian, fallopian tube or primary peritoneal cancer who were recurrent platinum intolerant, or with platinum resistant disease defined as radiological evidence of disease progression within 6 months of the last receipt of platinum based chemotherapy.

High Grade Serous Ovarian Cancer

Advanced non small cell lung cancer (NSCLC) defined as locally advanced and recurrent or metastatic, histologically confirmed NSCLC, and must have received at least 1 prior regimen for advanced/metastatic disease.

Non Small Cell Lung Cancer

Metastatic castration resistant prostate cancer (mCRPC) defined as histologically or cytologically confirmed adenocarcinoma of the prostate that has progressed after androgen deprivation therapy.

Metastatic Other Tumor Type Castration Resistant Prostate Cancer

Histologically confirmed HNSCC from any primary site; locally advanced disease (ie, persistent or progressive disease following curative intent radiation, and not a candidate for surgical salvage due to incurability or morbidity), or metastatic disease.

Head and Neck Squamous Cell Carcinoma

Any locally advanced or metastatic, histologically or cytologically proven solid tumor or NHL, that had relapsed after or progressing despite conventional treatment for which no conventional therapy was considered appropriate by the investigator or had been declined by the subject.

Other Tumor Type

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

American Indian or Alaska Native

Asian

Black or African American

Native Hawaiian or Other Pacific Islander

White

Other

Not Reported

Race/Ethnicity, Customized

United Kingdom

Region of Enrollment

The Safety Evaluable Population includes all enrolled subjects who receive at least 1 dose of SRA737.

GSK Response Center

As specified in the Statistical Analysis Plan, the frequency of each AE was evaluated in the overall Safety Evaluable Population rather than by tumor type subgroups with the intention of displaying the overall safety profile of SRA737 in advanced solid tumors. The Safety Evaluable Population includes all enrolled subjects who receive at least 1 dose of SRA737.

Number of Subjects With Adverse Events as Assessed by CTCAE 4.03

The Dose Escalation Phase included a total of 18 subjects in 9 different dosage cohorts: 20 mg QD, 40 mg QD, 80 mg QD, 160 mg QD, 300 mg QD, 600 mg QD, 1000 mg QD, 500 mg BID, and 1300 mg QD.

Dose Escalation Phase

In order to determine the MTD, a total of 18 subjects were enrolled in the dose escalation phase of the study in 9 dosage cohorts. All subjects receiving at least 75% of planned doses of SRA737 within Cycle 1 and those subjects receiving less than these planned doses of SRA737 due to DLT were considered evaluable for dose review decisions.

Maximum Tolerated Dose of SRA737

All 107 subjects treated in the study were included in the review of toxicity, PK and PDn, data in order to determine the RP2D. All clinically relevant toxicity, PK and PDn data up to 30 days after last dose of SRA737 were taken into account.

Recommended Phase 2 Dose of SRA737

The Response Evaluable Population (REP) included all enrolled subjects who satisfy all of the following conditions:

1. Measurable disease and assessment at baseline
2. Received at least 75% of 1 cycle of study medication, based on dosing information
3. At least one post baseline disease assessment OR discontinued treatment due to AE or disease progression or death

Disease Control Rate (DCR) of SRA737

Time to Progression (TTP)

Progression Free Survival (PFS)

Metastatic Castration Resistant Prostate Cancer

All subjects included in the Response Evaluable Population

Overall

The Response Evaluable Population (REP) included all subjects who satisfy the following conditions:

1. Measurable disease and assessment at baseline
2. Received at least 75% of 1 cycle of study medication, based on dosing information
3. At least 1 post baseline disease assessment OR discontinued treatment due to AE or disease progression or death Note: The median OS was not estimated in the mCRPC, HNSCC, or "Other" tumor type subgroups due to insufficient number of participants with events.

Overall Survival (OS)

Overall Study

Urinary Bladder Neoplasms

Antineoplastic Agents

Paclitaxel

Docetaxel

Albumin-Bound Paclitaxel

Sacituzumab govitecan

Tubulin Modulators

Antimitotic Agents

Immunoconjugates

Immunologic Factors

IDE397

IDEAYA Clinical Trials

Maroof Khan Zafar

New Patient Services

Teresa Lund

Estefania Bobe Cortes

Heather Flynn

Carol Goldener

Kailene Sullivan

Brandon Smith

Benjamin Herzberg, MD

Alexandra Mavracick

Christina Seunath

Benedito Carneiro

askSARAH

Jordi Rodon, MD

Carmen Gonzalez

Jia Liu

Ganessan Kichenadasse

Antoine Italiano

Eulalie Magne

Laurent Greillier

Thibault De la Motte Rouge

Frank Knauer

Ki Hyeong Lee

Ji-Youn Han

Joo-Hang Kim

Hye Ryun Kim

Changmin Choi

Montserrat Pequera Juvany

Elisa Lorente

Marta Benitez

Jorge Mercado

Laura Bailach

Ya-Zong Hsu

Chia-Chi Lin

Jasgit Sachdev, MD

This is a Phase 1, open-label, multicenter, dose escalation and expansion study of the safety, PK, PD, and preliminary anti-tumor activity of IDE397 as a single agent and in combination with other anticancer agents including taxanes (docetaxel, paclitaxel), or sacituzumab govitecan (SG), in adult patients with selected advanced or metastatic MTAP-deleted advanced solid tumors who are unresponsive to standard of care therapy. IDE397 is a small molecule inhibitor of methionine adenosyltransferase 2 alpha (MAT2A).

Study of IDE397 in Participants With Solid Tumors Harboring MTAP Deletion

An Open Label, Phase 1, Treatment Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of IDE397 (MAT2A Inhibitor) In Adult Participants With Advanced Solid Tumors

Incidence of DLTs of IDE397 will be determined

Incidence of DLTs of IDE397 in a combination setting will be determined

MTD and RP2D of IDE397 will be determined

MTD and RP2D of IDE397 in a combination setting will be determined

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase 1/2 Study of MRTX1719 in Solid Tumors With MTAP Deletion	NCT05245500	Mesothelioma Non Small Cell ... Malignant Perip... Solid Tumor Pancreatic Aden... Advanced Solid ...	MRTX1719	18 Years -	Mirati Therapeutics Inc.
A Phase 1/2 Trial of SRA737 in Subjects With Advanced Cancer	NCT02797964	Advanced Solid ...	SRA737	18 Years -	Sierra Oncology LLC - a GSK company
A Phase 1/2 Trial of SRA737 in Subjects With Advanced Cancer	NCT02797964	Advanced Solid ...	SRA737	18 Years -	Sierra Oncology LLC - a GSK company
Study of IDE397 in Participants With Solid Tumors Harboring MTAP Deletion	NCT04794699	Solid Tumor	IDE397 Docetaxel Paclitaxel Sacituzumab gov...	18 Years -	IDEAYA Biosciences
Niraparib in High-grade Endometrial Cancer Trial	NCT05289648	Endometrial Can... Serous Adenocar... Uterine Neoplas...	Niraparib oral ...	18 Years -	Sir Mortimer B. Davis - Jewish General Hospital
S095035 in Adult Participants With Advanced or Metastatic Solid Tumors With Deletion of the Methylthioadenosine Phosphorylase (MTAP) Gene	NCT06188702	MTAP-deleted So...	S095035	18 Years -	Servier

Spots Global Cancer Trial Database for synthetic lethality