| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| p53 Wild-Type (p53WT) Merkel Cell Carcinoma (MCC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Merkel Cell Carcinoma (MCC) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064025 |
| E.1.2 | Term | Merkel cell carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- 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 |
|
| E.2.2 | Secondary objectives of the trial |
- 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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 |
|
| E.4 | Principal 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 |
|
| E.5 End points |
| E.5.1 | 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 with avelumab.
- Cohort 2 Part 2: ORR will be assessed per RECIST criteria version 1.1
- Cohort 3: ORR as assessed per RECIST criteria version 1.1 based on independent review committee (IRC) review of tumor assessments.
- Cohort 4: ORR as assessed per RECIST criteria version 1.1 based on IRC review of tumor assessments. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Response Assessment: Response to KRT-232 treatment will be determined by the investigator according to RECIST criteria version 1.1. Target and non-target lesions will be assessed at Screening and followed throughout the study at protocol-specified time points. Response assessments will be performed at Week 5, Week 10, Week 15, Week 20, Week 25, Week 30 and thereafter every 12 weeks until disease progression. Response assessments should be performed at the specified time points independent of cycle visit or treatment modifications. For Cohorts 3 and 4, suspected progression must be confirmed by the IRC prior to treatment discontinuation. |
|
| E.5.2 | 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) |
|
| E.5.2.1 | 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 to 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: Days 1, 8, 15, 22 (for 28 D Cycle); Cycle 4 and beyond on Day 1 of each cycle
AEs: Every visit
Blood for PK: At time points specified in Appendix I of protocol |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Phase 1b/2, Open-Label Study |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Canada |
| Korea, Republic of |
| United States |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study will be considered complete 1 year after the last subject is enrolled in the study, at which time subjects who remain on study treatment will be evaluated for eligibility to enroll in a rollover study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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