p53 Wild-Type (p53WT) Merkel Cell Carcinoma (MCC) MedDRA version: 21.1 Level: LLT Classification code 10064025 Term: Merkel cell carcinoma System Organ Class: 100000004864
Conditions
Interventions
Product Name: Navtemadlin (KRT-232)
Product Code: KRT-232 with active ingredient content of 10%
Pharmaceutical Form: Tablet
INN or Proposed INN: Navtemadlin
CAS Number: 1352066-68-2
Current Sponsor co
Sponsors
Kartos Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. For Cohorts 1, 3 and 4, subjects must have failed treatment with at least one PD-1 inhibitor or PD-L1 inhibitor for metastatic MCC 2. For Cohort 2, subjects must not have received any anti-PD-1 or anti-PD-L1 treatments for metastatic MCC 3. For Cohort 3, subjects must not have received any prior chemotherapy. 4. For Cohort 4, subjects must have received at least 1 line of prior chemotherapy 5. Adults = 18 years of age and willing to provide written informed consent 6. ECOG performance status of 0 to 1 7. Histologically confirmed MCC. Disease must be measurable, with at least 1 measurable lesion by RECIST criteria, version 1.1 8. For Cohorts 1 and 2: MCC expressing p53WT based on any CLIA or FDA approved sequencing test or by a test approved by the local health authority or, if not available, by a validated test. For Cohort 2, subjects may be enrolled and treated with avelumab monotherapy before p53WT status is known 9. For Cohorts 3 and 4: MCC expressing p53WT based on Central Laboratory testing 10. Fresh or archival tumor tissue must be submitted for biomarker assessment. 11. Adequate hematological, hepatic, and renal function within 14 days prior to the first dose of KRT-232 as defined in more detail in the protocol 12. Agree to comply with contraception requirements as defined in more detail in the protocol Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 87 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 88
Exclusion criteria
Exclusion criteria: 1. For Cohort 2, subjects must not have autoimmune disease, medical conditions requiring systemic immunosuppression, prior stem cell transplant, or active infection with HBV or HCV 2. Concurrent anticancer treatment such as chemotherapy, cytoreductive therapy, immune therapy, or cytokine therapy within 28 days or approximately 5 half-lives, whichever is shorter, prior to the first dose of KRT-232 3. Radiation therapy within 2 weeks prior to the first dose of KRT-232 4. Toxicity from prior radiation therapy that has not resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 0 or Grade 1 (with the exception of Grade 2 alopecia) 5. Participation in another interventional clinical trial within the past 4 weeks of the first dose of KRT 232 (participation in observational studies is permitted) 6. Patients previously treated with MDM2 antagonist therapies or p53-directed therapies 7. Women who are pregnant or breastfeeding 8. History of major organ transplant 9. Subjects with known central nervous system (CNS) metastases that are previously untreated 10. Uncontrolled intercurrent illness including, but not limited to, acute hepatitis A; known history of human immunodeficiency virus (HIV)-positive; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements 11. Subjects with clinically significant bacterial, fungal, parasitic, or viral infection that requires therapy. Subjects with acute bacterial infections requiring antibiotic use should delay screening/ enrollment until the course of antibiotic therapy has been completed. 12. Other malignancy within the last 3 years, other than chronic lymphocytic leukemia (CLL), curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated nonmetastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma. Patients with CLL must not in the opinion of the investigator require or be receiving any treatment for their CLL in order to be eligible. 13. Grade 2 or higher QTc prolongation (>480 milliseconds per NCI-CTCAE criteria, version 5.0) 14. Known hypersensitivity or contraindications to any of the study drugs, required prophylaxes or their excipients
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - Cohort 1 Part 1: To determine the KRT-232 recommended phase 2 dose (RP2D) - Cohort 1 Part 2: To determine the objective response rate (ORR) in subjects with p53WT MCC who have failed anti-PD-1 or anti-PD-L1 immunotherapy - Cohort 2 Part 1: To determine the KRT-232 RP2D in combination with avelumab - Cohort 2 Part 2: To determine the objective response rate (ORR) in treatment-naïve subjects with p53WT MCC}-Cohort 3: To determine the confirmed objective response rate (ORR) in subjects with p53WT MCC who are chemotherapy naïve and who have failed anti-PD-1 or anti-PDL-1 immunotherapy -Cohort 4: To determine the confirmed objective response rate (ORR) in subjects with p53WT MCC who have failed anti-PD-1 or anti-PDL-1 immunotherapy and who have received at least 1 line of prior chemotherapy;Secondary Objective: Cohort 3: To determine the objective response rate (ORR) in subjects with p53WT MCC who are chemotherapy naïve and who have failed anti-PD-1 or anti-PDL-1 immunotherapy-Cohort 4: To determine the objective response rate (ORR) in subjects with p53WT MCC who have failed anti-PD-1 or anti-PDL-1 immunotherapy and who have received at least 1 line of prior chemotherapy - To determine duration of response (DoR) - To determine progression-free survival (PFS) - To determine overall survival (OS) - To determine the clinical benefit rate (CBR) - To determine KRT-232 safety and tolerability - To determine the pharmacokinetic/pharmacodynamic (PK/PD) profile of KRT-232;Primary end point(s): - Cohort 1 Part 1: Safety Review Committee (SRC) will determine recommended phase 2 dose (RP2D) for expansion based on safety and tolerability of each arm. - Cohort 1 Part 2: Objective Response Rate (ORR) as assessed per RECIST criteria version 1.1 - Cohort 2 Part 1: Dose Limiting toxicity (DLT) will be used to establish the Maximum Tolerated Dose (MTD) of KRT-232 in combination with avelumab. SRC will determine the RP2D based on the safety of combination of KRT-232 wit | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Cohort 3: ORR as assessed per RECIST criteria version 1.1 based on investigator assessment. - Cohort 4: ORR as assessed per RECIST criteria version 1.1 based on investigator assessment. - Median DoR (Kaplan-Meier estimate) among subjects who achieve a response from the first observation of response to disease progression per IRC or investigator assessment, or death. - Median time from the first study dose to disease progression per IRC or investigator assessment, or death and landmark PFS rate (%)(Kaplan-Meier estimate) - Median time from the first study dose to death (Kaplan-Meier estimate) and landmark survival rate (%) - CBR is defined among subjects who achieve PR, CR or stable disease that lasts at least 10 weeks, per IRC or investigator assessment. - Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, and AEs that led to KRT-232 dose reductions, interruptions or discontinuations, AEs, serious AEs (SAEs), ECGs, vital signs - KRT-232 and acyl glucuronide metabolite (M1) PK parameters, including but not limited to, maximum observed concentration (Cmax), minimum observed concentration (Cmin), area under the plasma concentration-time curve (AUC), and terminal elimination half-life (t1/2z);Timepoint(s) of evaluation of this end point: DoR: Time from documentation of response until disease progression per IRC or investigator assessment, or death. PFS: Time from initial treatment until disease progression per IRC or investigator assessment, or death. OS: Time from initial treatment until death Vital signs: Day 1 of each cycle ECOG performance status: Day 1 of each cycle as per ECOG performance status scale ECG Triplicate: Cycle 1 Day 1, Cycle 3 Day 1, Cycle 6 Day 1, Cycle 9 Day 1, and every 3rd cycle thereafter (21 D Cycle) ECG Triplicate: Cycle 1 Day 1, Cycle 3 Day 1, Cycle 6 Day 1, and every 3rd cycle thereafter (28 D Cycle) Hematology: Cycle 1, 2, and 3: D | — |
Countries
France, Germany, Italy, Netherlands, Spain, United States
Contacts
Public ContactEmily Houlihan
Kartos Therapeutics, Inc.
Outcome results
None listed