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

This study will have 2 parts.

Primary Outcome Measures

1. Number of Participants Experiencing Dose-Limiting Toxicity (DLT)
   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.
2. Part 1: Number of Participants Who Experience an Adverse Event (AE)
   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.
3. Part 1: Number of Participants Who Discontinue Study Treatment Due to an AE
   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.
4. Progression Free Survival (PFS)
   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

1. Objective Response Rate (ORR)
   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.
2. Overall Survival (OS)
   OS is defined as the time from randomization to death due to any cause.
3. Duration of Response (DOR)
   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.
4. Part 2: Number of Participants with an Adverse Event (AE)
   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.
5. Part 2: Number of Participants who Discontinue Study Treatment Due to an AE
   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.
6. 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
   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.
7. Change from Baseline in the EORTC-QLQ-C30 Physical Functioning (Items 1-5) Combined Score
   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.
8. Change from Baseline in the EORTC-QLQ-C30 Role Functioning (Items 6 and 7) Combined Score
   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.
9. Change from Baseline in the EORTC-QLQ-C30 Appetite Loss (Item 13) Score
   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.
10. Change from Baseline in the EORTC-Quality of Life Questionnaire-Colorectal Cancer-Specific 29 Items (QLQ-CR29) Bloating (Item 37) Score
    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.
11. Time to First Deterioration (TTD) in EORTC QLQ-C30 Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score
    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.
12. TTD in EORTC QLQ-C30 Physical Functioning (Items 1-5) Score
    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.
13. TTD in EORTC QLQ-C30 Role Functioning (Items 6 and 7) Score
    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.
14. TTD in EORTC QLQ-C30 Appetite Loss (Item 13) Score
    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.
15. TTD in EORTC QLQ-CR29 Bloating (Item 37) Score
    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.