Primary Objectives- 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…
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- 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.
Secondary outcome
- 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)
Background summary
Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with a poor
prognosis in patients with advanced disease. The 5-year disease-associated
mortality is 46% (Lemos 2010). The recommended treatment modality for MCC
depends on the character of the disease. For local
disease, surgery is the mainstay of treatment, together with post-operative
radiation. For metastatic disease, programmed cell death protein-1/programmed
death ligand-1 (PD-1/PD-L1) blockade is recommended. For patients with
metastatic disease and contraindications to
checkpoint immunotherapy, various cytotoxic chemotherapy regimens are used.
There is a significant unmet need for improved therapies for patients with MCC
who have failed treatment with at least one anti- PD-1 or anti-PD-L1
immunotherapy. KRT-232 is an orally bioavailable, small molecule, targeted drug
that binds to murine double minute 2 homologue (MDM2) and inhibits the
MDM2/tumor protein 53 (p53) protein-protein interaction. KRT-232 has been shown
to inhibit the growth of p53 wild type (p53WT) tumor cells in vitro and tumor
xenografts in vivo. p53 is a tumor suppressor and transcription factor that
responds to cellular stress by activating the transcription of numerous genes
involved in cell cycle arrest, apoptosis, senescence, and deoxyribonucleic acid
(DNA) repair. Preclinically, the key determinant of sensitivity to MDM2
inhibition is the p53 mutational status of cells, with p53WT cells being
sensitive to such inhibitors. Mutations in p53 have rarely been found in MCC
tumors (Sihto 2011), suggesting that
a majority of patients with MCC are p53WT and thus may be responsive to
inhibition of the MDM2/p53 proteinprotein interaction.
Study objective
Primary Objectives
- 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
Study design
The study will evaluate the safety and efficacy of KRT-232 and KRT-232 in
combination with avelumab in subjects with p53WT MCC. Subjects will be enrolled
into 4 cohorts. A Safety Review Committee (SRC) will review the safety data
during the study.
- Cohort 1 (KRT-232 monotherapy; N = up to 61 subjects)
- Cohort 2: KRT-232 in combination with avelumab (N = up to 39 subjects)
- Cohort 3: KRT-232 monotherapy (N = 50 subjects)
- Cohort 4: KRT-232 monotherapy (N = 25 subjects)
Intervention
KRT-232, a murine double minute chromosome 2 (MDM2) inhibitor that prevents
MDM2/tumor protein 53 (p53) protein-protein interaction.
Avelumab, a programmed death ligand-1 (PD-L1) blocking antibody, administered
according to the local prescribing label.
Study burden and risks
This is a Phase 1b/2, open-label study of KRT-232 in subjects with p53
wild-type (p53WT) MCC who have failed anti-PD-1 or anti-PD-L1 immunotherapy or
are anti-PD-1 or anti-PD-L1 treatment naive.
Dosing for KRT-232 and/or avelumab will be held or modified if suspected
adverse drug reactions, changes in vital signs, ECGs, or clinical laboratory
results are observed and these changes pose a significant health risk.
Clinically or medically significant suspected adverse drug events, and serious
adverse events (SAEs) regardless of relationship to study drug will be followed
until resolved or considered stable.
The study may be terminated at any point in time at the discretion of the
Sponsor. See Sections 6.1 and 6.2 for dose holding and modification
guidelines. See Section 10.12 for safety stopping rules.
Subjects will be treated until disease progression or lack of tolerability. The
definition of disease progression is based on RECIST criteria version 1.1
(Appendix 4).
All subjects who discontinue study treatment for any reason other than disease
progression will be followed for response and survival. Those who discontinue
because of disease progression will be followed for survival. (see Schedule of
Assessments, Appendix 1).
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.
The study is expected to take between 1 and 2 years in total for a patient. A
biopsy from MCC tissue is required to verify eligibility. Furthermore,
recording of drug intake in a diary and additional physical examinations will
be required. This concerns additional pregnancy testing (for women) and
potentially additional CT scans. Anyhow, additional blood samples will be
required. In total, around 760 mL blood will be taken in 1.5 year.
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Age
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. Failure is defined as any
subject whose disease has progressed (by RECIST criteria) or those who are
intolerant to PD-1 inhibitor or PD-L1 inhibitor treatment. Any PD-1 inhibitor
or PD-L1 inhibitor may have been used at any time in the past, with no limit or
minimum duration required.
2. For Cohort 2, subjects must not have received any anti-PD-1 or
anti-PD-L1therapy.
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 (Eisenhauer 2009, Appendix 4).
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
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, organconfined 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
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-002820-35-NL |
| ClinicalTrials.gov | NCT03787602 |
| CCMO | NL78594.056.21 |