Evaluation of Revumenib in Participants With Colorectal Cancer and Other Solid Tumors

Phase 2TerminatedNCT05731947

Syndax Pharmaceuticals41 enrolled

Overview

This study will evaluate the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of revumenib in participants with colorectal cancer (CRC) or other solid tumors who have failed at least 1 prior line of therapy.

The study will be conducted in two parts. The Phase 1 portion of the study consists of a dose escalation cohort, and a signal-seeking expansion where anti-tumor activity signals will be evaluated. The Phase 2 portion of the study will further confirm the anti-tumor activity signals of revumenib.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Colorectal Cancer Solid Tumors

Interventions

RevumenibDRUG

Revumenib administered orally with or without food. Participants may continue to receive treatment until disease progression or until they experience unacceptable toxicity.

ChemotherapyDRUG

Either Lonsurf® or Stivarga® administered per the investigator's choice at the respective drug label's dose and schedule. Participants may continue to receive treatment until disease progression or until they experience unacceptable toxicity.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: * Male and female participants aged ≥18 years * Participants with metastatic CRC or other solid tumors * Evidence of locally recurrent or metastatic disease based on imaging studies within 28 days of cycle 1/day 1 (C1D1) * CRC participants must have had at least one line of standard-of-care therapy and must have progressed on or been intolerant to, or unable to receive, oxaliplatin, irinotecan, and bevacizumab in the advanced/metastatic setting. * Other solid tumor participants must have had all approved standard therapies that are available to the participant, unless contraindicated or intolerable. * Participants must have experienced documented unequivocal progressive disease by either RECIST v1.1 or clinical assessment, or experienced unacceptable toxicity with their prior therapy. * Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1 * If receiving radiation therapy, has had a 2-week washout period following completion of the treatment prior to receiving the C1D1 dose and continues to have at least 1 measurable lesion * At least 42 days since prior immunotherapy, including tumor vaccines and checkpoint inhibitors, and at least 21 days since receipt of chimeric antigen receptor therapy or other modified T-cell therapy * Adequate bone marrow, renal, cardiac, and liver function Key Exclusion Criteria: * Participant has a prior history of malignant bowel obstruction requiring hospitalization in the 6 months prior to enrollment * Participant has a history of uncontrolled ascites, defined as symptomatic ascites and/or repeated paracenteses for symptom control in the past 3 months * Detectable human immunodeficiency virus (HIV) viral load within the previous 6 months. Participants with a known history of HIV 1/2 antibodies must have viral load testing prior to study enrollment * Hepatitis B and/or C * Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Classification Class ≥II), life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack * Corrected QT interval (QTc) \>450 milliseconds * Any gastrointestinal (GI) issue of the upper GI tract likely to affect oral drug absorption or ingestion (for example, gastric bypass, gastroparesis) * Cirrhosis with a Child-Pugh score of B or C * Brain metastasis except for those participants who have completed definitive therapy, are not on steroids, have a stable neurologic status for at least 4 weeks after completion of the definitive therapy and steroids, and do not have neurologic dysfunction that would confound the evaluation of neurologic and other adverse events (AEs) * History of or any concurrent condition, therapy, laboratory abnormality, or allergy to excipients that in the Investigator's opinion might confound the results of the study, interfere with the participant's ability to participate for the full duration of the study, or not be in the best interest of the participant to participate * Participant has received prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study baseline or who has not recovered (that is, ≤Grade 1 or at baseline) from AEs related to a previously administered agent. * Participation in another therapeutic interventional clinical study in which an investigational agent was administered within 30 days before starting revumenib * Participant has received a transfusion of blood products or administration of colony stimulating factors within 4 weeks of the first dose of the study drug * History of additional malignancy within the prior 5 years, excluding adequately treated basal cell carcinoma, squamous cell of the skin, cervical intraepithelial neoplasia/cervical carcinoma in situ, or melanoma in situ or ductal carcinoma in situ of the breast

Locations (6)

Honor Health Research Institute

Scottsdale, Arizona, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Memorial Sloan Kettering Cancer Center

Manhattan, New York, United States

Gabrail Cancer Center

Canton, Ohio, United States

Outcomes

Primary Outcomes

Phase 1a: Number of Participants Experiencing Dose Limiting Toxicities (DLTs)

DLT was defined as any of the following occurring in Cycle 1: Grade 4 neutropenia (absolute neutrophil count \[ANC\] \<500 cells/mm\^3) unresolved to Grade 2 (ANC \>1500 cells/mm\^3) or baseline for more than 7 consecutive days in the absence of growth factor support, ≥Grade 3 neutropenia (ANC \<1000 cells/mm\^3) with a single temperature of \>38.3°Celsius (101°Fahrenheit) or a sustained temperature of ≥38°Celsius (100.4°Fahrenheit) for more than 1 hour, Grade 4 thrombocytopenia (\<25,000/mm\^3) of any duration, ≥Grade 3 thrombocytopenia (\<50,000/mm\^3) with clinically significant bleeding, Grade 4 anemia (i.e, life-threatening consequences; urgent intervention indicated) or ≥Grade 3 nonhematologic toxicity as defined in Common Terminology Criteria for Adverse Events version 5.0 scale where Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, medically significant, Grade 4=Life-threatening and 5=Death.

Time frame: Day 1 up to Day 28

Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE was therefore any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of the study intervention, whether or not considered related to the study intervention. TEAEs were defined as those having an onset on or after the first dose of revumenib or a sign, symptom, or a diagnosis that worsened on or after first dose of revumenib but no later than 30 days after the date of the last dose of revumenib. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.

Time frame: Up to 2.2 years

Phase 1: Disease Control Rate (DCR)

DCR was defined as the percentage of participants with objective evidence of confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD) according to Response Evaluation in Solid Tumors (RECIST) version 1.1 criteria as assessed by the investigator. CR=disappearance of all target lesions; disappearance of non-target lesions. PR=At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. PD=At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions.

Data from ClinicalTrials.gov

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Secondary Outcomes

Phase 1a: Maximum Plasma Concentration (Cmax) of Revumenib

Time frame: Cycle 1 Day 7, Cycle 1 Day 14, Cycle 2 Day 8, Cycle 2 Day 15, Cycle 5 Day 1 (Cycle length=28 days)

Phase 1b: Maximum Plasma Concentration (Cmax) of Revumenib

Time frame: Cycle 1 Day 7, Cycle 1 Day 14, Cycle 2 Day 8, Cycle 2 Day 15 (Cycle length=28 days)

Phase 1a: Area Under the Plasma Concentration Versus Time Curve (AUC0-t) of Revumenib

Time frame: Cycle 1 Day 7, Cycle 1 Day 14, Cycle 2 Day 8, Cycle 2 Day 15, Cycle 5 Day 1 (Cycle length=28 days)

Phase 1a: Time to Maximum Plasma Concentration (Tmax) of Revumenib

Time frame: Cycle 1 Day 7, Cycle 1 Day 14, Cycle 2 Day 8, Cycle 2 Day 15, Cycle 5 Day 1 (Cycle length=28 days)

Phase 1b: Time to Maximum Plasma Concentration (Tmax) of Revumenib

Time frame: Cycle 1 Day 7, Cycle 1 Day 14, Cycle 2 Day 8, Cycle 2 Day 15 (Cycle length=28 days)

Phase 1b: Area Under the Plasma Concentration Versus Time Curve (AUC0-t) of Revumenib

Time frame: Cycle 1 Day 7, Cycle 1 Day 14, Cycle 2 Day 8, Cycle 2 Day 15 (Cycle length=28 days)

Phase 2: Area Under The Concentration Time Curve of Revumenib

Time frame: Up to 2.2 years

Phase 2: Maximum Plasma Concentration (Cmax) of Revumenib

Time frame: Up to 2.2 years

Phase 2: Time to Maximum Plasma Concentration (Tmax) of Revumenib

Time frame: Up to 2.2 years

Phase 2: Number of Participants With TEAEs

An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE was therefore any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of the study intervention, whether or not considered related to the study intervention. TEAEs were defined as those having an onset on or after the first dose of revumenib or a sign, symptom, or a diagnosis that worsened on or after first dose of revumenib but no later than 30 days after the date of the last dose of revumenib. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.

Time frame: Up to 2.2 years

Phase 2: Overall Survival (OS)

OS was defined as the time from the date of first dosing of revumenib to death due to any cause.

Time frame: Up to 2.2 years

Phase 2: Disease Control Rate (DCR) at 6 Cycles (28-Day Cycles) as Assessed by Blinded Radiographic Review

DCR was defined as the percentage of participants with objective evidence of confirmed CR, confirmed PR, or SD according to RECIST version 1.1 criteria as assessed by blinded radiographic review. CR=disappearance of all target lesions; disappearance of non-target lesions. PR=At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. PD=At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions.

Time frame: Up to 2.2 years

Phase 2: ORR as Assessed by Blinded Radiographic Review

ORR was defined as the percentage of participants who achieved a best overall response of PR or CR according to RECIST v1.1 criteria as assessed by blinded radiographic review. PR=At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. CR=Disappearance of all target lesions; disappearance of all nontarget lesions.

Time frame: Up to 2.2 years

Phase 2: Duration of Response (DOR) as Assessed by Blinded Radiographic Review

DOR was defined as the time from the first documented response (CR or PR) to the first documented objective PD or death due to any case according to RECIST v1.1 criteria as assessed by blinded radiographic review. PR=At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. CR=Disappearance of all target lesions; disappearance of all nontarget lesions. PD=At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions.

Time frame: Up to 2.2 years

Phase 2: Disease Control Rate (DCR) at 6 Cycles (28-Day Cycles) as Assessed by the Investigator

DCR was defined as the percentage of participants with objective evidence of confirmed CR, confirmed PR, or SD according to RECIST version 1.1 criteria as assessed by investigator. CR=disappearance of all target lesions; disappearance of non-target lesions. PR=At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. PD=At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions.

Time frame: Up to 2.2 years

Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator

ORR was defined as the percentage of participants who achieved a best overall response of PR or CR according to RECIST v1.1 criteria as assessed by investigator. PR=At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. CR=Disappearance of all target lesions; disappearance of all nontarget lesions.

Time frame: Up to 2.2 years

Phase 2: DOR as Assessed by the Investigator

DOR was defined as the time from the first documented response (CR or PR) to the first documented objective PD or death due to any case according to RECIST v1.1 criteria as assessed by investigator. PR=At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. CR=Disappearance of all target lesions; disappearance of all nontarget lesions. PD=At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions.

Time frame: Up to 2.2 years