A Study of Calderasib (MK-1084) in KRAS Mutant Advanced Solid Tumors (MK-1084-001)

Official title

A Phase 1, Open-label, Multicenter Study to Assess Safety, Tolerability, PK, and Efficacy of MK-1084 as Monotherapy and as Part of Various Combination Therapies in Participants With KRAS G12C Mutant Advanced Solid Tumors

Overview

This is a study evaluating the safety, pharmacokinetics, and efficacy of calderasib alone, and calderasib plus other combination therapies in participants with advanced solid tumors with identified kirsten rat sarcoma viral oncogene homolog G12C (KRAS G12C) mutation.

Interventions

• Drug Calderasib
  Oral dose
• Biological Pembrolizumab
  Intravenous infusion of 200 mg
• Drug carboplatin
  Per label
• Drug pemetrexed
  Per label
• Biological cetuximab
  Per label
• Drug oxaliplatin
  Per label
• Drug leucovorin
  Per label
• Drug 5-fluorouracil
  Per label

Primary outcome measures

• Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) [Time frame: Up to ~21 days]
• Number of Participants Who Experience an Adverse Event (AE) [Time frame: Up to ~56 months]
• Number of Participants Who Discontinue Study Treatment Due to an AE [Time frame: Up to ~56 months]

Secondary outcome measures (9)

• Objective Response Rate (ORR) [Time frame: Up to ~56 months]
• Duration of Response (DOR) [Time frame: Up to ~56 months]
• Mean Plasma Concentration of calderasib [Time frame: At designated timepoints during the study in Cycles 1, 2, 3, 5, 9, 13, 17, 21, 25, and every 6 weeks thereafter up to 56 months. Cycle=3 weeks (Arms 1-4) and 4 weeks (Arms 5-6)]
• Maximum Concentration (Cmax) of calderasib [Time frame: At designated timepoints during the study in Cycles 1, 2, 3, 5, 9, 13, 17, 21, 25, and every 6 weeks thereafter up to 56 months. Cycle=3 weeks (Arms 1-4) and 4 weeks (Arms 5-6).]
• Time to Maximum Concentration (Tmax) of calderasib [Time frame: At designated timepoints during the study in Cycles 1, 2, 3, 5, 9, 13, 17, 21, 25, and every 6 weeks thereafter up to 56 months. Cycle=3 weeks (Arms 1-4) and 4 weeks (Arms 5-6)]
• Minimum Concentration (Cmin) of calderasib [Time frame: At designated timepoints during the study in Cycles 1, 2, 3, 5, 9, 13, 17, 21, 25, and every 6 weeks thereafter up to 56 months. Cycle=3 weeks (Arms 1-4) and 4 weeks (Arms 5-6)]
• Area Under the Concentration Time-Curve 0-12 Hours (AUC 0-12) of calderasib [Time frame: At designated timepoint during the study in Cycle 1 Day 1: Predose and up to 12 hours postdose. Cycle=3 weeks (Arms 1-4) and 4 weeks (Arms 5-6)]
• Area Under the Concentration Time-Curve 0-24 Hours (AUC 0-24) of calderasib [Time frame: At designated timepoint during the study in Cycle 1 Day 1: Predose and up to 24 hours postdose. Cycle=3 weeks (Arms 1-4) and 4 weeks (Arms 5-6)]
• Half-Life (t1/2) of calderasib [Time frame: At designated timepoint during the study in Cycle 1 Day 1: Predose and up to 24 hours postdose. Cycle=3 weeks (Arms 1-4) and 4 weeks (Arms 5-6)]

Eligibility criteria

Inclusion criteria

For all participants:

• Has measurable disease by RECIST 1.1 criteria
• Has adequate organ function
• Male participants agree to protocol-specified contraception requirements including refraining from donating sperm and using protocol-specified contraceptives unless confirmed to be azoospermic
• Female participants must not be pregnant or breastfeeding, and must agree to protocol-specified contraceptive requirements and must have a negative highly sensitive pregnancy test within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention

For Arm 1 - Has locally advanced unresectable or metastatic solid-tumor malignancy with histologically OR blood-based confirmation of KRAS G12C mutation who has received at least 1 line of therapy for systemic disease

For Arm 2

\- Has an untreated metastatic non-small cell lung cancer (NSCLC) with histologically OR blood-based confirmation of KRAS G12C mutation and histologic confirmation of programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1%

For Arm 3

• Has locally advanced unresectable or metastatic solid-tumor malignancy with histological or blood-based confirmation of KRAS G12C mutation who has received at least 1 line of therapy for systemic disease Expansion Group A: 2L+NSCLC
• Has histologically or cytologically confirmed diagnosis of unresectable or metastatic NSCLC with histological or blood-based confirmation of KRAS G12C mutation and submits archival tumor sample
• Previous treatment failure of at least 1 line of systemic therapy Expansion Group B
• Has locally advanced unresectable or metastatic solid-tumor malignancy, excluding NSCLC or CRC, with histologically or blood- based confirmation of KRAS G12C mutation who has received at least 1 line of therapy for systemic disease

Arm 4 only - Has an untreated advanced or metastatic nonsquamous NSCLC with histologically or blood-based confirmation of KRAS G12C mutation

Arm 5 only

• Histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic colorectal adenocarcinoma and with histologically or blood-based confirmation of KRAS G12C mutation
• Previous treatment failure of one or 2 previous line(s) of systemic therapy

Arm 6 only

\- Locally advanced unresectable or metastatic colorectal adenocarcinoma with histologically or blood-based confirmation of KRAS G12C mutation

Exclusion criteria

• Has received chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) before first dose of study intervention
• Has a history of second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 5 years
• Has clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has an active infection requiring systemic therapy
• Known history of HIV infection or. has a known history of Hepatitis B virus or known active Hepatitis C virus infection
• Has a history of interstitial lung disease, noninfectious pneumonitis requiring active steroid therapy, or ongoing pneumonitis
• Has an active autoimmune disease requiring systemic therapy
• Has not fully recovered from any effects of major surgical procedure without significant detectable infection
• Has one or more of the following ophthalmological findings/conditions: intraocular pressure >21 mm Hg and/or any diagnosis of glaucoma; diagnosis of central serous retinopathy, retinal vein occlusion, or retinal artery occlusion and/or a diagnosis of retinal degenerative disease excluding age-related macular degeneration
• Has received live or live-attenuated vaccine within 4 weeks of study start

Arm 4 Only

• Is unable to interrupt aspirin or other nonsteroidal anti-inflammatories (NSAIDs), other than an aspirin dose ≤1.3 grams per day, for at least 2 days (5 days for long-acting agents \[for example, piroxicam\]) before, during, and for at least 2 days after administration of pemetrexed.
• Is unable/unwilling to take folic acid, vitamin B12, and dexamethasone

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 9 centers

• Beijing Friendship Hospital Affiliate of Capital University-Oncology ( Site 0417) — Beijing
• Fujian Cancer Hospital ( Site 0419) — Fuzhou
• Southern Medical University Nanfang Hospital-Depatrment of Respiratory and Critical Care M — Guangzhou
• Sun Yat-sen University Cancer Center-Internal medicine ( Site 0415) — Guangzhou
• Union Hospital Tongji Medical College Huazhong University of Science and Technology ( Site — Wuhan
• Jilin Cancer Hospital-oncology department ( Site 0412) — Changchun
• Shanghai Chest Hospital-Oncology department ( Site 0410) — Shanghai
• Shanghai East Hospital ( Site 0416) — Shanghai
• … and 1 more center

United States · 6 centers

• Moffitt Cancer Center ( Site 0261) — Tampa
• START Midwest ( Site 0267) — Grand Rapids
• John Theurer Cancer Center at Hackensack University Medical Center ( Site 0260) — Hackensack
• Laura and Isaac Perlmutter Cancer Center ( Site 0270) — New York
• NEXT Virginia ( Site 0271) — Fairfax
• MEDICAL COLLEGE OF WISCONSIN-Cancer Center Clinical Trials Office ( Site 0262) — Milwaukee

Ukraine · 6 centers

• MNPE ClinCenter of Oncology,Hematology,Transplantology and Palliative Care of CherkasyRegC — Cherkasy
• Communal Non-Commercial Enterprise Prykarpatski Clinical Onc-Chemotherapy department ( Sit — Ivano-Frankivsk
• Private Enterprise Private Manufacturing Company Acinus-Medical and Diagnostic Centre ( Si — Kropyvnytskyi
• Rivne Regional Clinical Hospital ( Site 0257) — Rivne
• ME RIVNE REGIONAL ANTITUMOR CENTER ( Site 0259) — Rivne
• Uzhhorod Multispecialty City Clinical Hospital ( Site 0258) — Uzhhorod

Canada · 5 centers

• Cross Cancer Institute ( Site 0033) — Edmonton
• The Moncton Hospital ( Site 0037) — Moncton
• Hamilton Health Sciences-Juravinski Cancer Centre ( Site 0030) — Hamilton
• Kingston Health Sciences Centre-Kingston General Hospital Site ( Site 0036) — Kingston
• Princess Margaret Cancer Centre-Division of Medical Oncology and Hematology ( Site 0032) — Toronto

Israel · 5 centers

• Rambam Health Care Campus-Oncology ( Site 0090) — Haifa
• Shaare Zedek Medical Center-Oncology ( Site 0092) — Jerusalem
• Hadassah Medical Center-Oncology ( Site 0094) — Jerusalem
• Meir Medical Center. ( Site 0091) — Kfar Saba
• Sheba Medical Center-ONCOLOGY ( Site 0093) — Ramat Gan

Japan · 5 centers

• National Cancer Center Hospital East ( Site 0404) — Kashiwa
• Kanagawa Cancer Center ( Site 0402) — Yokohama
• Shizuoka Cancer Center ( Site 0401) — Nakatogari
• National Cancer Center Hospital ( Site 0403) — Chuo-ku
• Cancer Institute Hospital of JFCR ( Site 0400) — Koto

Australia · 4 centers

• Chris O'Brien Lifehouse ( Site 0002) — Camperdown
• Liverpool Hospital-Medical Oncology ( Site 0001) — Liverpool
• Westmead Hospital ( Site 0006) — Westmead
• Monash Health-Oncology Research ( Site 0003) — Clayton

Chile · 4 centers

• James Lind Centro de Investigacion del Cancer ( Site 0043) — Temuco
• Centro de Estudios Clínicos SAGA-CECSAGA ( Site 0041) — Santiago
• FALP-UIDO ( Site 0040) — Santiago
• Bradfordhill ( Site 0042) — Santiago

Poland · 4 centers

• Uniwersytecki Szpital Kliniczny w Poznaniu ( Site 0172) — Poznan
• Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Oddzial Badan Wczesnych Faz ( — Warsaw
• Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 0171) — Gdansk
• Oddzial Onkologii Klinicznej z Pododdzialem Chemioterapii Jednodniowej ( Site 0173) — Koszalin

Turkey (Türkiye) · 4 centers

• Ege University Medicine of Faculty ( Site 0231) — Bornova
• Erciyes University ( Site 0232) — Talas
• Hacettepe Universite Hastaneleri-oncology hospital ( Site 0234) — Ankara
• Ankara City Hospital-oncology ( Site 0233) — Ankara

Argentina · 3 centers

• Instituto Alexander Fleming ( Site 0434) — Ciudad Autónoma de Buenos Aires
• Sanatorio Parque ( Site 0456) — Rosario
• Fundación CORI para la Investigación y Prevención del Cáncer ( Site 0438) — La Rioja

Italy · 3 centers

• Humanitas ( Site 0113) — Rozzano
• ospedale le scotte-U.O.C. Immunoterapia Oncologica ( Site 0111) — Siena
• Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 0110) — Naples

Spain · 3 centers

• Clinica Universidad de Navarra ( Site 0213) — Madrid
• Hospital Universitario Fundación Jiménez Díaz-START Madrid-FJD ( Site 0211) — Madrid
• Hospital Universitari Vall d'Hebron-Oncology ( Site 0212) — Barcelona

Taiwan · 3 centers

• Chang Gung Memorial Hospital at Kaohsiung-Oncology and Hematology ( Site 0445) — Kaohsiung Niao Sung Dist
• National Cheng Kung University Hospital ( Site 0444) — Tainan
• National Taiwan University Hospital-Oncology ( Site 0443) — Taipei

Lithuania · 2 centers

• Hospital of Lithuanian University of Health Sciences Kauno klinikos ( Site 0121) — Kaunas
• Vilnius University Hospital Santaros Clinics Affiliate - National Cancer Center ( Site 012 — Vilnius

Panama · 2 centers

• Centro Oncologico de Panama ( Site 0160) — Panama City
• Centro Hemato Oncológico Paitilla ( Site 0163) — Panama City

South Korea · 2 centers

• Seoul National University Hospital ( Site 0191) — Seoul
• Samsung Medical Center-Division of Hematology/Oncology ( Site 0193) — Seoul

Switzerland · 2 centers

• Cantonal Hospital St.Gallen ( Site 0224) — Sankt Gallen
• Ospedale Regionale Bellinzona e Valli ( Site 0220) — Bellinzona

Denmark · 1 center

• Odense Universitetshospital-Department of oncology ( Site 0421) — Odense

Malaysia · 1 center

• Sarawak General Hospital ( Site 0453) — Kuching

New Zealand · 1 center

• New Zealand Clinical Research (Christchurch) ( Site 0004) — Christchurch

Publications

• Ma X, Sloman DL, Duggal R, Anderson KD, Ballard JE, Bharathan I, Brynczka C, Gathiaka S, Henderson TJ, Lyons TW, Miller R, Munsell EV, Orth P, Otte RD, Palani A, Rankic DA, Robinson MR, Sather AC, Solban N, Song XS, Wen X, Xu Z, Yang Y, Yang R, Day PJ, Stoeck A, Bennett DJ, Han Y. Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRASG12C Inhibitor. J Med Chem. 2024 Jul 11;67(13):11024-110 PMID 38924388

Identifiers

NCT: NCT05067283 · 1084-001 · MK-1084-001 · jRCT2041220034 · 2022-501563-40-00 · U1111-1281-2482

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗