With MSS/pMMR Advanced, Platinum-resistant Ovarian Cancer
Conditions
Brief summary
This is an open-label, single-arm, investigator-initiated study conceived as a dose expansion cohort of the study D3-002, which evaluated ETC-159 in combination with pembrolizumab in solid tumors.
Detailed description
Hypothesis: Wnt pathway inhibition with ETC-159 in combination PD1 checkpoint inhibition is safe and effective for the treatment of patients with advanced MSS/pMMR ovarian cancer.It is hypothesized that, ETC-159, as a selective PORCNi, will lead to increased immune infiltration and therefore may turn cold tumors into hot tumors that may then be responsive to checkpoint inhibitor Primary Objectives: 1. To evaluate the preliminary clinical activity of ETC-159 in combination with pembrolizumab according to RECIST v1.1, in patients with advanced or metastatic, platinum-resistant MSS/pMMR ovarian cancer 2. To assess the safety of ETC-159 at the dose of 8 mg every other day (the recommended dose \[RD\] identified in safety segment) in combination with pembrolizumab. Secondary Objectives: 1. To further assess the efficacy of ETC-159 in combination with pembrolizumab 2. To evaluate the PK of ETC-159 in combination with pembrolizumab in patients. Exploratory Objectives: 1. To evaluate the effect of ETC-159 administered orally every other day in combination with pembrolizumab with bone protective treatment (denosumab and subsequently zoledronic acid if no response is observed with denosumab) on bone turnover markers as potential downstream markers of Wnt signaling (β-CTX). 2. To correlate available tumor genomic profile with clinical data. 3. To evaluate the effect of ETC-159 treatment on : * Pharmacodynamic biomarker (Axin2 mRNA expression levels) in hair follicles. * Gene expression levels and PD-L1 protein expression measured in FFPE-tumor tissue (if sufficient tissue is available). 4. To determine change in serum levels of cancer antigen 125 (CA-125).
Interventions
DRUGETC-159
ETC-159 will be administered orally.
DRUGPembrolizumab
Pembrolizumab will be administered intravenously.
DRUGDenosumab / Zoledronic Acid
Denosumab will be administrated subcutaneously. Zoledronic Acid will be administered intravenously if denosumab has no response.
Sponsors
EDDC (Experimental Drug Development Centre), A*STAR Research Entities
National University Hospital, Singapore
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Patients will undergo screening procedures to determine eligibility within 28 days prior to the initial administration of ETC-159 in combination with pembrolizumab. ETC-159 in combination with pembrolizumab will be administered in 21-day cycles (1 cycle: 21 days). ETC-159 will be dosed every other day. Pembrolizumab will be dosed IV Q3W. Tumor response assessments will be done every 6 weeks (2 cycles) prior to starting the cycle starting at C3D1 (- 7 days) until C9D1 (- 7 days); thereafter every 12 weeks (4 cycles) starting at C13D1 (- 7 days) and at EOT, until disease progression or start of another anti-cancer therapy according to RECIST v1.1.
Eligibility
Sex/Gender
FEMALE
Age
21 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Is capable of understanding the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with the protocol requirements. 2. Is female, and age 21 years or older (Singapore sites) at pre-screening or screening. 3. Has histologically or cytologically confirmed, advanced or metastatic ovarian cancer with a platinum free interval of less than 6 months from prior platinum based treatment or for whom platinum therapy is no longer an option according to the treating physician 4. Has MSS/pMMR tumors as determined by immunohistochemistry (IHC), polymerase chain reaction (PCR), or next-generation sequencing (NGS). 5. Has objective (assessable through clinical signs, symptoms, and/or laboratory findings) and radiologically-confirmed progression of disease at Screening. 6. Has measurable disease as determined by RECIST v1.1 (Appendix 4, Section 12.4). Target lesions should not be selected in previously irradiated fields unless there is clear evidence of progression. 7. Has ECOG performance of status 0 to 2 at Screening. 8. Has life expectancy of at least 3 months at Screening. 9. Has adequate organ function at Screening, including the following (noting that repeated tests Screening should not be performed unless there are sufficient reasons to assume the patient would meet the inclusion criteria with re-testing). * Absolute neutrophil count ≥1.0 × 109/L * Platelet count ≥100 × 109/L (without transfusions within 21 days prior to Day 1 of Cycle 1 * Hemoglobin ≥9 g/dL * Prothrombin time and partial thromboplastin time within ≤1.5 × upper limit of normal (ULN) * International normalized ratio (INR) ≤1.5 × ULN Note: If the patient is on allowed anti-coagulants the INR and coagulation parameters should be in the therapeutic range * Total bilirubin ≤1.5 × ULN * Transaminases (AST and/or alanine aminotransferase ≤2.5 × ULN (\<5 × ULN if liver metastases) * Calculated creatinine clearance ≥40 mL/min (Cockroft and Gault formula) * Total calcium (corrected for serum albumin) within normal limits prior to Day 1 of Cycle 1 (supplementation is permitted). Note: Patients with grade 1 changes can be included as long as they are asymptomatic and can receive supplementation during the study. o Magnesium ≥the lower limit of normal (LLN) prior to Day 1 of Cycle 1 (supplementation is permitted). Note: Patients with grade 1 changes can be included as long as they are asymptomatic and can receive supplementation during the study. 10. Patients must have a T-score greater than -1 to be eligible, however, patients with osteopenia (defined as a T-score of -1 to -2.5 at the left or right total hip, left or right femoral neck, or lumbar spine \[L1 to L4\] as determined by DEXA at Screening) are eligible to participate and will receive calcium and vitamin D supplements during the study. Patients with osteoporosis (T-score of \<-2.5) must be excluded. Note: T-score should be calculated according to local requirements by DEXA scan for the purpose of determining eligibility. 11. Is capable of swallowing study medication and following directions regarding taking study drug or has a daily caregiver who will be responsible for administering study drug. 12. Has a negative serum pregnancy test at Screening or a negative urine pregnancy test within 7 days prior to Day 1 Cycle 1 prior of treatment (applies to females of childbearing potential only). 13. For all patients: pre-dose and post-dose tumor biopsies are mandatory unless tumor is inaccessible or deemed unsafe for procedure by the principal investigator. Note: NGS reports can be collected where biopsies are not done.
Exclusion criteria
Subjects should not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | 1 Year | is defined as percentage of subjects with best overall response as (Complete Response (CR) + Partial Response (PR) + Stable disease ≥12 weeks) evaluated by RECIST v1.1 criteria measured by CT or MRI |
| Objective Response Rate (ORR) | 1 Year | is defined as percentage of subjects with best overall response as (Complete Response (CR) + Partial Response (PR)) evaluated by RECIST v1.1 criteria measured by CT or MRI |
Countries
Singapore
Contacts
Primary ContactShao peng David Tan
Backup ContactTan
Outcome results
None listed