A Clinical Study of MK-1084 With Targeted Therapy and Chemotherapy in People With Colorectal Cancer (MK-1084-012/KANDLELIT-012)

Phase 3

Recruiting

• Conditions: Colon Adenocarcinoma; Rectal Adenocarcinoma
• Interventions: Drug: MK-1084; Drug: Oxaliplatin; Drug: Leucovorin/levofolinate calcium; Drug: 5-Fluorouracil; Drug: Bevacizumab; Biological: Cetuximab

• Registration Number: NCT06997497
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

Researchers are looking for other ways to treat locally advanced or metastatic colorectal cancer (mCRC) that is unresectable and has a gene mutation called KRAS G12C.

Standard (or usual) treatments for this type of colorectal cancer may include mFOLFOX6 with or without bevacizumab. Researchers want to learn if adding MK-1084 (the study medicine) and cetuximab to mFOLFOX6 can treat locally advanced or mCRC with the KRAS G12C mutation. MK-1084 and cetuximab are targeted therapies.

The goals of this study are to learn:

* About the safety of MK-1084 with cetuximab and mFOLFOX6 and if people tolerate the treatments

* If people who receive MK-1084 with cetuximab and mFOLFOX6 live longer without mCRC growing or spreading compared to people who receive mFOLFOX6 with or without bevacizumab.

Detailed Description

This study will have 2 parts.

Study Timeline

• Study First Submitted: 2025-05-21
• Study First Submitted QC: 2025-05-21
• Study First Posted: 2025-05-30
• Study Start: 2025-07-16
• Status Verified: 2025-09
• Last Update Submitted: 2025-09-08
• Last Update Posted: 2025-09-10
• Primary Completion: 2029-08-27
• Study Completion: 2030-10-27

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 477

Inclusion Criteria

The main inclusion criteria include but are not limited to the following:

• Has a histologically confirmed diagnosis of locally advanced unresectable or metastatic (unresectable Stage III or Stage IV as defined by American Joint Committee on Cancer [AJCC] eighth edition) colorectal adenocarcinoma
• Part 2 only: Has not received systemic anticancer therapy for locally advanced unresectable or metastatic colorectal cancer
• Tumor tissue demonstrates presence of a Kirsten rat sarcoma viral oncogene homolog G12C (KRAS G12C) mutation
• Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART)
• Participants who are Hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy and have undetectable HBV viral load
• Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable

Exclusion Criteria

The main exclusion criteria include but are not limited to the following:

• Has active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, chronic diarrhea)
• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease
• Has known dihydropyrimidine dehydrogenase (DPD) deficiency
• HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
• Has received prior systemic anticancer therapy including investigational agents within 4 weeks before randomization
• Has 1 or more conditions that, in the opinion of the investigator, make the participant ineligible for treatment with bevacizumab
• Has known additional malignancy that is progressing or has required active treatment within the past 3 years
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis or leptomeningeal disease
• Has active infection requiring systemic therapy
• Has not adequately recovered from major surgery or have ongoing surgical complications
• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MK-1084 + Cetuximab + mFOLFOX6	MK-1084	Participants will receive MK-1084 orally once daily (QD), cetuximab per label every 2 weeks (Q2W), and mFOLFOX6 chemotherapy: oxaliplatin per label every 2 weeks (Q2W), leucovorin or levofolinate calcium per label Q2W, and 5-fluorouracil (5-FU) per label Q2W. Treatment will continue until criteria for discontinuation is met.
MK-1084 + Cetuximab + mFOLFOX6	Oxaliplatin	Participants will receive MK-1084 orally once daily (QD), cetuximab per label every 2 weeks (Q2W), and mFOLFOX6 chemotherapy: oxaliplatin per label every 2 weeks (Q2W), leucovorin or levofolinate calcium per label Q2W, and 5-fluorouracil (5-FU) per label Q2W. Treatment will continue until criteria for discontinuation is met.
MK-1084 + Cetuximab + mFOLFOX6	Leucovorin/levofolinate calcium	Participants will receive MK-1084 orally once daily (QD), cetuximab per label every 2 weeks (Q2W), and mFOLFOX6 chemotherapy: oxaliplatin per label every 2 weeks (Q2W), leucovorin or levofolinate calcium per label Q2W, and 5-fluorouracil (5-FU) per label Q2W. Treatment will continue until criteria for discontinuation is met.
MK-1084 + Cetuximab + mFOLFOX6	5-Fluorouracil	Participants will receive MK-1084 orally once daily (QD), cetuximab per label every 2 weeks (Q2W), and mFOLFOX6 chemotherapy: oxaliplatin per label every 2 weeks (Q2W), leucovorin or levofolinate calcium per label Q2W, and 5-fluorouracil (5-FU) per label Q2W. Treatment will continue until criteria for discontinuation is met.
MK-1084 + Cetuximab + mFOLFOX6	Cetuximab	Participants will receive MK-1084 orally once daily (QD), cetuximab per label every 2 weeks (Q2W), and mFOLFOX6 chemotherapy: oxaliplatin per label every 2 weeks (Q2W), leucovorin or levofolinate calcium per label Q2W, and 5-fluorouracil (5-FU) per label Q2W. Treatment will continue until criteria for discontinuation is met.
mFOLFOX6	Oxaliplatin	Participants will receive mFOLFOX6 chemotherapy: oxaliplatin per label Q2W, leucovorin or levofolinate calcium per label Q2W, and 5-fluorouracil (5-FU) per label Q2W. Participants may also receive bevacizumab Q2W at the investigator's discretion. Treatment will continue until criteria for discontinuation is met.
mFOLFOX6	Leucovorin/levofolinate calcium	Participants will receive mFOLFOX6 chemotherapy: oxaliplatin per label Q2W, leucovorin or levofolinate calcium per label Q2W, and 5-fluorouracil (5-FU) per label Q2W. Participants may also receive bevacizumab Q2W at the investigator's discretion. Treatment will continue until criteria for discontinuation is met.
mFOLFOX6	5-Fluorouracil	Participants will receive mFOLFOX6 chemotherapy: oxaliplatin per label Q2W, leucovorin or levofolinate calcium per label Q2W, and 5-fluorouracil (5-FU) per label Q2W. Participants may also receive bevacizumab Q2W at the investigator's discretion. Treatment will continue until criteria for discontinuation is met.
mFOLFOX6	Bevacizumab	Participants will receive mFOLFOX6 chemotherapy: oxaliplatin per label Q2W, leucovorin or levofolinate calcium per label Q2W, and 5-fluorouracil (5-FU) per label Q2W. Participants may also receive bevacizumab Q2W at the investigator's discretion. Treatment will continue until criteria for discontinuation is met.

Primary Outcome Measures

Name	Time	Method
Number of Participants Experiencing Dose-Limiting Toxicity (DLT)	Up to approximately 28 days	A DLT is defined as the occurrence of protocol-specified toxicities if assessed by the investigator to be possibly, probably, or definitely related to study intervention administration.
Part 1: Number of Participants Who Experience an Adverse Event (AE)	Up to approximately 6 years	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Part 1: Number of Participants Who Discontinue Study Treatment Due to an AE	Up to approximately 6 years	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Progression Free Survival (PFS)	Up to approximately 4 years	PFS is defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Up to approximately 3 years	ORR is defined as a confirmed complete response (CR: the disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR). The percentage of participants who experience CR or PR as assessed by BICR will be presented.
Overall Survival (OS)	Up to approximately 5 years	OS is defined as the time from randomization to death due to any cause.
Duration of Response (DOR)	Up to approximately 4 years	For participants who demonstrate a confirmed 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) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by BICR will be presented.
Part 2: Number of Participants with an Adverse Event (AE)	Up to approximately 6 years	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Part 2: Number of Participants who Discontinue Study Treatment Due to an AE	Up to approximately 6 years	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC)-Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score	Baseline and up to approximately 6 years	The EORTC QLQ-C30 is a cancer specific health-related quality-of life (QoL) questionnaire. Participant responses to the questions regarding Global Health Status (GHS; "How would you rate your overall health during the past week?") and Quality of Life (QoL; "How would you rate your overall quality of life during the past week?") are scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in GHS (EORTC QLQ-C30 Item 29) and QoL (EORTC QLQ-C30 Item 30) combined score will be presented. A higher score indicates a better outcome.
Change from Baseline in the EORTC-QLQ-C30 Physical Functioning (Items 1-5) Combined Score	Baseline and up to approximately 6 years	The EORTC QLQ-C30 is a cancer specific health-related quality-of-life questionnaire. Participant responses to 5 questions about their physical functioning (Items 1-5) are scored on a 4-point scale (1=Not at All to 4=Very Much). Higher scores indicate better physical functioning. The change from baseline in EORTC QLQ-C30 Physical Functioning (Items 1-5) combined score will be presented.
Change from Baseline in the EORTC-QLQ-C30 Role Functioning (Items 6 and 7) Combined Score	Baseline and up to approximately 6 years	The EORTC QLQ-C30 is a cancer specific health-related quality-of-life questionnaire. The role functioning score is based on participant responses to questions scored on a 4-point scale (1=Not at All to 4=Very Much). Higher scores indicate better role functioning. The change from baseline in EORTC QLQ-C30 Role Functioning (Items 6 and 7) combined score will be presented.
Change from Baseline in the EORTC-QLQ-C30 Appetite Loss (Item 13) Score	Baseline and up to approximately 6 years	The EORTC QLQ-C30 is a cancer specific health-related quality-of life questionnaire, including a single-item scale score for appetite loss (QLQ-C30 Item 13). For this item, individual responses to the question "Have you lacked appetite?" are given on a 4-point scale (1=Not at all; 4=Very much). Scores are transformed to a range from 0-100, with a lower score indicating a better outcome. The change from baseline in the EORTC QLQ-C30 appetite loss (Item 13) scale score will be presented.
Change from Baseline in the EORTC-Quality of Life Questionnaire-Colorectal Cancer-Specific 29 Items (QLQ-CR29) Bloating (Item 37) Score	Baseline and up to approximately 6 years	The EORTC QLQ-CR29 is a health-related quality-of life questionnaire specific for colorectal cancer, including a single-item scale score for bloating (QLQ-CR29 Item 37). For this item, individual responses to the question "Did you have a bloated feeling in your abdomen?" are given on a 4-point scale (1=Not at all; 4=Very much). Scores are transformed to a range from 0-100, with a lower score indicating a better outcome. The change from baseline in the EORTC QLQ-CR29 bloating (Item 37) scale score will be presented.
Time to First Deterioration (TTD) in EORTC QLQ-C30 Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score	Baseline and up to approximately 6 years	The EORTC QLQ-C30 is a cancer specific health-related quality-of-life questionnaire. TTD is defined as the time from baseline to the first onset of a ≥10-point deterioration (decrease) from baseline in global health status (GHS) (EORTC QLQ-C30 Item 29) \& quality of life (QoL) combined score (EORTC QLQ-C30 Item 30). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from baseline in GHS and QoL combined score, will be presented. A longer TTD indicates a better outcome.
TTD in EORTC QLQ-C30 Physical Functioning (Items 1-5) Score	Baseline and up to approximately 6 years	The EORTC QLQ-C30 is a cancer specific health-related quality-of-life questionnaire. TTD is defined as the time from baseline to the first onset of a ≥10-point deterioration (decrease) from baseline in physical functioning score (EORTC QLQ-C30 Items 1-5). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from baseline in GHS and QoL combined score, will be presented. A longer TTD indicates a better outcome.
TTD in EORTC QLQ-C30 Role Functioning (Items 6 and 7) Score	Baseline and up to approximately 6 years	The EORTC QLQ-C30 is a cancer specific health-related quality-of-life questionnaire. The role functioning score is based on participant responses to questions scored on a 4-point scale (1 = 'Not at All' to 4 = 'Very Much'). Higher scores indicate better role functioning. The TTD, as assessed based on a ≥10-point negative change (decrease) from baseline in role functioning score, will be presented. A longer TTD indicates a better outcome.
TTD in EORTC QLQ-C30 Appetite Loss (Item 13) Score	Baseline and up to approximately 6 years	The EORTC QLQ-C30 is a cancer specific health-related quality-of-life questionnaire. TTD is defined as the time from baseline to the first onset of a ≥10-point deterioration (decrease) from baseline in appetite loss score (EORTC QLQ-C30 Item 13). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from baseline in physical functioning score, will be presented. A longer TTD indicates a better outcome.
TTD in EORTC QLQ-CR29 Bloating (Item 37) Score	Baseline and up to approximately 6 years	The EORTC QLQ-CR29 is a health-related quality-of life questionnaire specific for colorectal cancer, including a single-item scale score for bloating (QLQ-CR29 Item 37). TTD is defined as the time from baseline to the first onset of a ≥10-point deterioration (decrease) from baseline in bloating score (QLQ-CR29 Item 37). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from baseline in appetite loss score, will be presented. A longer TTD indicates a better outcome.

Trial Locations

Locations (18)

Renown Regional Medical Center ( Site 0056); 🇺🇸 Reno, Nevada, United States

Fundacion Estudios Clinicos ( Site 0105); 🇦🇷 Rosario, Santa Fe Province, Argentina

Sun Yat-Sen University Cancer Center ( Site 0800); 🇨🇳 Guangzhou, Guangdong, China

RMNE "Bukovyna Clinical Oncology Center" ( Site 1709); 🇺🇦 Chernivtsi, Chernivetska Oblast, Ukraine

MNPE "Prykarpattia Clinical Oncology Center of Ivano-Frankivsk Regional Council" ( Site 1701); 🇺🇦 Ivano-Frankivsk, Ivano-Frankivsk Oblast, Ukraine

CNE "Regional Clinical Oncology Center of the Kirovohrad Regional Council" ( Site 1702); 🇺🇦 Kropyvnytskyi, Kirovohrad Oblast, Ukraine

MNPE LTMU Multidisc. Clin. Hosp. of Emerg. and Intens. Care ( Site 1708); 🇺🇦 Lviv, Lviv Oblast, Ukraine

MNE "Central City Hospital" ( Site 1711); 🇺🇦 Rivne, Rivne Oblast, Ukraine

Uzhgorod Central City Clinical Hospital ( Site 1700); 🇺🇦 Uzhhorod, Zakarpattia Oblast, Ukraine

Medical Center "Universal Clinic "Oberig" of Limited Liability Company "Kapytal" ( Site 1704); 🇺🇦 Kyiv, Ukraine

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