A Master Protocol for the Multi-Cohort, Phase 1/2 Study of DCC-3116 in Combination with Anticancer Therapies in Participants with Advanced Malignancies

Details

IRB Study Number 23-780

Status Recruiting

Institute Taussig Cancer Institute

Description

6.1.1. Primary Objectives

Part 1 (Safety/Dose-finding):

• To evaluate the safety and tolerability of DCC-3116 in combination with module-specific anticancer therapies

• To determine recommended dose(s) and/or the MTD of DCC-3116 in combination with module-specific anticancer therapies

Part 2 (Expansion):

• To evaluate the objective response rate of combination therapy at recommended dose(s) in each expansion cohort using histology-specific consensus response criteria (eg, RECIST [Response Evaluation Criteria in Solid Tumors] v1.1)

6.1.2. Secondary Objectives

Part 1 (Safety/Dose-finding):

• To evaluate the anticancer activity of DCC-3116 in combination with module-specific anticancer therapies using histology-specific consensus response criteria

• To characterize the PK of DCC-3116 and module-specific anticancer therapies

Part 2 (Expansion):

• To further characterize the efficacy of DCC-3116 at recommended dose(s) in combination with module-specific anticancer therapies

• To evaluate the safety and tolerability of DCC-3116 in combination with module-specific anticancer therapies

• To characterize the PK of DCC-3116 and module-specific anticancer therapies in expansion cohorts

Inclusion Criteria

ModuleA

Male or female ≥18 years of age
Must have pathologically confirmed CRC with a documented mutation in BRAF V600E. A molecular pathology report documenting mutational status of BRAF V600E must be available at Screening
Eligible to receive cetuximab per locally approved label with regard to tumor RAS status. A molecular pathology report documenting mutational status of RAS must be available at Screening
Must have received at least 1 and not more than 2 lines of prior systemic therapy (the maintenance portion of a systemic therapy is not counted as a separate line of therapy) in the advanced or metastatic setting (relapse during adjuvant therapy or within 6 months of completion of adjuvant therapy will be considered metastatic disease). Must not have received prior treatment with an epidermal growth factor receptor or BRAF inhibitor
Must have a life expectancy of more than 3 months in the judgment of the Investigator
Must have at least 1 measurable lesion according to RECIST v1.1
Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening
Adequate organ function and bone marrow reserve as indicated by the following laboratory assessments at Screening by the central laboratory:

i. Bone Marrow Function: Absolute neutrophil count ≥1500/μL; hemoglobin ≥9 g/dL; platelet count ≥75,000/μL

ii. Hepatic Function: Total serum bilirubin ≤1.5×the upper limit of normal (ULN) except for participants with known Gilbert’s syndrome, who may have total serum bilirubin <3×ULN; serum aspartate aminotransferase and alanine aminotransferase ≤2.5×ULN. Alkaline phosphatase ≤2.0×ULN

iii. Renal Function: Creatinine clearance ≥50 mL/min based either on measured 24-hour urine clearance or Cockcroft Gault estimation

iv. Coagulation Function: Prothrombin time, international normalized ratio, and partial thromboplastin time or activated partial thromboplastin time ≤1.5×ULN Note: Participants on a vitamin K antagonist anticoagulant maintenance regimen may have prothrombin time /international normalized ratio measurements >1.5×ULN if, in the opinion of the Investigator, the participant is suitable for the study and the Investigator assesses that such therapy can be interrupted, at acceptable risk, for collection of tumor biopsies at Screening and at Cycle 2 Day 1

v. Corrected serum calcium of >8.0 mg/dL; serum sodium >130 mmol/L; serum albumin >3 g/dL

Must provide a fresh tumor biopsy from a primary or metastatic cancer lesion that can be biopsied with acceptable risk as determined by the Investigator during the Screening Period and an archival tumor tissue sample, if available (preferably collected after last anticancer therapy). If a fresh tumor biopsy is not possible, then an archival tumor tissue sample must be provided
Must agree to provide an on treatment (Cycle 2 Day 1) biopsy if a cancer lesion can be biopsied with acceptable risk as determined by the Investigator
Must be able to take oral medication
Female participants of reproductive potential must have a negative serum beta-human chorionic gonadotropin pregnancy test at Screening and a negative pregnancy test at Cycle 1 Day 1 (C1D1) prior to the first dose of study drug
Participants of reproductive potential must agree to follow the contraception requirements outlined in Section 8.4.2
Participants must be capable of understanding and complying with the protocol, and participants must have signed the informed consent form (ICF) before any study-specific procedures are performed

ModuleB

Male or female ≥18 years of age
Only for Part 1 (Safety/Dose-finding):

i.Must have pathologically confirmed GIST with a documented mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA). A molecular pathology report documenting the mutational status of KIT or PDGFRA must be available at Screening

ii.Must have progressed on at least one approved systemic regimen given in the locally advanced or metastatic setting or have documented intolerance to it. Participants must not have received prior ripretinib treatment but may have received prior alternate tyrosine kinase inhibitors or other systemic therapy for GIST. Examples of conditions that could be considered intolerance are severe toxicity despite appropriate dose reductions and optimal symptom management or persistent low-grade adverse events that do not prevent the participant from continuing therapy but that may adversely impact function and quality of life

Only for Part 2 (Expansion):

i.Must have pathologically confirmed GIST with a documented mutation in KIT exon 11. A molecular pathology report documenting mutational status of exon 11 must be available at Screening

ii.Must have progressed on imatinib given in the locally advanced or metastatic setting or have been intolerant to imatinib and may not have received additional systemic therapy for GIST. Examples of conditions that could be considered imatinib intolerance are severe toxicity despite appropriate dose reductions and optimal symptom management or persistent low-grade adverse events that do not prevent the participant from continuing therapy with imatinib but that may adversely impact function and quality of life

Must have a life expectancy of more than 3 months in the judgment of the Investigator
Must have at least 1 measurable lesion according to mRECIST
Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening
Adequate organ function and bone marrow reserve as indicated by the following laboratory assessments at Screening by the central laboratory:

i.Bone Marrow Function: Absolute neutrophil count ≥1500/μL; hemoglobin ≥9 g/dL; platelet count ≥75,000/μL

ii.Hepatic Function: Total serum bilirubin ≤1.5×the upper limit of normal (ULN) except for participants with known Gilbert’s syndrome, who may have total serum bilirubin <3×ULN; serum aspartate aminotransferase and alanine aminotransferase ≤2.5×ULN. Alkaline phosphatase ≤2.0×ULN

iii.Renal Function: creatinine clearance ≥50 mL/min based either on measured 24-hour urine clearance or Cockcroft Gault estimation

iv.Coagulation Function: Prothrombin time, international normalized ratio, and partial thromboplastin time or activated partial thromboplastin time ≤1.5×ULN Note: Participants on a vitamin K antagonist anticoagulant maintenance regimen may have PT/international normalized ratio measurements >1.5×ULN if, in the opinion of the Investigator, the participant is suitable for the study and the Investigator assesses that such therapy can be interrupted, at acceptable risk, for collection of tumor biopsies at Screening and at Cycle 2 Day 1

v.Corrected serum calcium of >8.0 mg/dL; serum sodium >130 mmol/L; serum albumin >3 g/dL

Must provide a fresh tumor biopsy from a primary or metastatic cancer lesion that can be biopsied with acceptable risk as determined by the Investigator during the Screening Period and an archival tumor tissue sample, if available (preferably collected after last anticancer therapy). If a fresh tumor biopsy is not possible, then an archival tumor tissue sample must be provided
Must agree to provide an on treatment (Cycle 2 Day 1) biopsy if a cancer lesion can be biopsied with acceptable risk as determined by the Investigator
Must be able to take oral medication
Female participants of reproductive potential must have a negative serum beta-human chorionic gonadotropin pregnancy test at Screening and a negative pregnancy test at Cycle 1 Day 1 prior to the first dose of study drug
Participants of reproductive potential must agree to follow the contraception requirements outlined in Section 8.4.2
Participants must be capable of understanding and complying with the protocol, and participants must have signed the ICF before any study-specific procedures are performed

Exclusion Criteria

ModuleA

Must not have received the following within the specified time periods prior to the first dose of study drug:

i. Medications, including anticancer therapies, that are known strong or moderate inhibitors or inducers of CYP3A4 or P-glycoprotein (P-gp) including certain herbal medications (eg, St. John’s wort): 14 days or 5×the half-life of the medication (whichever is longer)

ii. Other anticancer therapies and any investigational therapies with a known safety and PK profile: 14 days or 5×the half-life of the medication (whichever is shorter)

iii. Investigational therapies with unknown safety and PK profile: 28 days. If there is enough data on the investigational therapy to assess the risk for drug-drug interactions and late toxicities of prior therapy as low, the Medical Monitor may approve a shorter washout of 14 days

iv. Grapefruit or grapefruit juice: 14 days

Have not recovered from all clinically relevant toxicities from prior therapy according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 to Grade ≤1 or participant baseline prior to the first dose of study drug. Participant baseline is defined as no change in severity grade within 28 days prior to signed informed consent
New York Heart Association Class III or IV heart disease, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension, congestive heart failure, or myocardial infarction within 6 months prior to the first dose of study drug
12-lead electrocardiogram demonstrating QT interval corrected by Fridericia's formula >450 ms in males or >470 ms in females at Screening or history of long QT syndrome
Systemic arterial thrombotic or embolic events, such as cerebrovascular accident (including ischemic attacks) or moderate hemoptysis within 6 months prior to the first dose of study drug
Systemic venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial events (eg, pulmonary embolism) within 3 months prior to the start of study drug or requirement of anticoagulation therapy that cannot be interrupted at acceptable risk, per assessment by the Investigator, for collecting tumor biopsies at Screening and on Cycle 2 Day 1
Symptomatic central nervous system (CNS) metastases or presence of leptomeningeal disease Note: A participant with previously treated brain metastases may participate pending Sponsor approval and provided that:

• They are stable (eg, no evidence of progression by magnetic resonance imaging [MRI]) for at least 4 weeks prior to the first dose of study drug (must be confirmed by MRI, with contrast, within 28 days of Cycle 1 Day 1). If there is a contraindication to MRI, CT with contrast may be used to document and confirm stability

• All neurologic symptoms have resolved or are stable for at least 4 weeks prior to the first dose of study drug

• Participants do not require steroid therapy for brain metastases for at least 4 weeks prior to the first dose of study drug Note: If signs or symptoms suggest CNS metastases, a brain MRI, with contrast, must be performed to confirm the absence of detectable CNS disease within 2 weeks prior to receiving study drug

Malabsorption syndrome or other illness that could affect oral absorption as judged by the Investigator
Bone disease that requires ongoing treatment or has required treatment, including radiation, bisphosphonates, and/or denosumab within 6 months of signing the ICF
Radiation for indications other than bone disease must have been completed 4 weeks prior to first dose of study drug, unless it consisted of limited field palliative radiation, including whole brain radiation, which must have been completed at least 2 weeks prior to first dose of study drug
Major surgery within 4 weeks of the first dose of study drug. All surgical wounds must be healed and free of infection or dehiscence before the first dose of the study drug
Any other clinically significant comorbidities, such as uncontrolled pulmonary disease, active infection, or any other condition that in the judgment of the Investigator could compromise compliance with the protocol, interfere with the interpretation of study results, or predispose the participant to safety risks
HIV infection unless all of the following requirements are met:

• CD4 count >350/μL

• No acquired immunodeficiency syndrome-defining opportunistic infection in the last 12 months

• Stable anti-retroviral regimen with medications that are not prohibited by the protocol for at least 4 weeks with HIV viral load less than 400 copies/mL prior to first dose of study drug

Hepatitis B virus (HBV) infection unless the HBV DNA viral load is negative, and the participant is on a stable HBV suppressive regimen with medications that are not prohibited by the protocol for at least 4 weeks prior to first dose of study drug. Participants with evidence for past HBV infection who are hepatitis B surface antigen negative, hepatitis B core antigen positive, and HBV DNA viral load negative without history of HBV treatment in the 12 months preceding signature of informed consent are eligible and should be monitored/treated as per local standard of care
Hepatitis C virus (HCV) infection unless the HCV RNA viral load is negative, and the participant has either completed curative HCV therapy or is on a stable HCV therapy regimen with medications that are not prohibited by the protocol for at least 4 weeks prior to first dose of study drug
Female participant is pregnant or breastfeeding
Ongoing participation in an interventional study. Ongoing participation in a noninterventional study (including observational studies) is permitted
Must not have received prior treatment with DCC-3116
Must not have received prior treatment with an EGFR or BRAF inhibitor
Known allergy or hypersensitivity to any component of DCC-3116 or any of its excipients. Please refer to the current version of the Investigator’s Brochure for list of excipients for DCC-3116
Known allergy or hypersensitivity to any component of encorafenib or cetuximab or any of their excipients. Please refer to the package inserts for encorafenib and cetuximab excipients

ModuleB

Must not have received the following within the specified time periods prior to the first dose of study drug:

i. Medications, including anticancer therapies that are known strong or moderate inhibitors or inducers of CYP3A4 or P-glycoprotein (P-gp) including certain herbal medications (eg, St. John’s wort): 14 days or 5×the half-life of the medication (whichever is longer)