Epithelial Ovarian Cancer, Gynecologic Neoplasms
Conditions
Keywords
PLX2853, Ovarian Cancer, ARID1A, Gynecological Malignancies, Carboplatin
Brief summary
The purpose of this research study is to evaluate safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of the investigational drug PLX2853 in Advanced Gynecological Malignancies with a Known ARID1A Mutation and PLX2853/Carboplatin Combination Therapy in Platinum-Resistant Epithelial Ovarian Cancer.
Interventions
DRUGPLX2853
PLX2853 tablets
DRUGCarboplatin
Carboplatin IV injection, 5 mg•min/mL
Sponsors
Opna Bio LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 years at the time of signing informed consent 2. Histologically or cytologically confirmed diagnosis of 1 of the following, and must have measurable disease per RECIST v1.1: * Phase 2a (PLX2853 monotherapy): Any advanced gynecological malignancy (cervical, vaginal, vulvar, uterine, ovarian, fallopian tube, or primary peritoneal) with a known ARID1A mutation, that is intolerant to or refractory to all standard therapy known to confer clinical benefit. * Phase 1b and Phase 2a (PLX2853 + carboplatin combination): Platinum-resistant EOC (including fallopian tube or primary peritoneal cancer). 3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1 4. Adequate organ function as demonstrated by laboratory values. 5. Women of child bearing potential (defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or is not postmenopausal) must have a negative serum pregnancy test within 7 days prior to taking the first dose of study drug and, if sexually active, must agree to use a highly effective method of contraception (a contraception method with a failure rate \<1% per year) and 1 additional barrier method from the time of the negative pregnancy test to 90 days after the last dose of study drug. Women of non-child bearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year. 6. Except as specified above for organ function, all drug-related toxicity from previous cancer therapy must be resolved (to Grade ≤1 or baseline per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 \[NCI CTCAE v5.0\]) prior to study treatment administration (Grade 2: alopecia, hot flashes, decreased libido, or neuropathy is allowed). 7. Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements
Exclusion criteria
1. Prior exposure to a bromodomain inhibitor 2. Ongoing systemic infection requiring treatment with antibiotic, antiviral, or antifungal treatment 3. Autoimmune hemolytic anemia or autoimmune thrombocytopenia 4. Presence of symptomatic or uncontrolled central nervous system or leptomeningeal metastases 5. Red blood cell or platelet transfusion within 14 days of Screening blood draw 6. Known or suspected allergy to the investigational agent or any agent given in association with this study 7. Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 μg (NIH-ODS 2020). 8. Use of strong inhibitors and inducers of CYP3A4 and 2C8 9. Clinically significant cardiac disease 10. Inability to take oral medication or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the Investigator, would preclude adequate absorption 11. Non-healing wound, ulcer, or bone fracture 12. Infection with HIV-1 or HIV-2. Exception: subjects with well-controlled HIV (e.g., CD4 \>350/mm3 and undetectable viral load) are eligible. 13. Current active liver disease from any cause, including hepatitis A (hepatitis A virus immunoglobulin M positive), hepatitis B (hepatitis B virus \[HBV\] surface antigen positive), or hepatitis C (hepatitis C virus \[HCV\] antibody positive, confirmed by HCV ribonucleic acid). 14. Active known second malignancy with the exception of any of the following: * Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer * Adequately treated Stage I cancer from which the subject is currently in remission and has been in remission for ≥2 years * Any other cancer from which the subject has been disease-free for ≥3 years 15. Major surgery or significant traumatic injury within 28 days prior to Cycle 1 Day 1 16. Hospitalization for subacute bowel obstruction within 28 days prior to Cycle 1 Day 1 17. Receipt of anti-cancer therapy prior to Cycle 1 Day 1: * Chemotherapy, radiation therapy, or small molecule anti-cancer therapy for the treatment of cancer within 14 days or 5 half-lives (whichever is shorter) of Cycle 1 Day 1 * Immune therapy or other biologic therapy (e.g., monoclonal antibodies, antibody-drug conjugates) for the treatment of cancer within 21 days or 5 half-lives (whichever is shorter) of Cycle 1 Day 1 Subjects can receive a stable dose of bisphosphonates for bone metastases, before and during the study as long as these were started at least 28 days prior to treatment with study drug. 18. Subject is participating in any other therapeutic clinical study (observational or registry studies are allowed). 19. Subjects who are pregnant or breast-feeding 20. Presence of any other medical, psychological, familial, sociological, or geographic condition potentially hampering compliance with the study protocol or would interfere with the study endpoints or the subject's ability to participate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2a (PLX2853 Monotherapy): Number of Participants With Overall Response Rate (ORR) as Measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | From 8 weeks of treatment for only PLX2853 (Cycle 3 Day 1; 28 days per cycle) until completion of long term follow-up, an average of 6 months. | Overall response rate as measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) |
| Phase 1b (PLX2853 + Carboplatin Combination): Establish the Number of Participants Reaching MTD/RP2D for the Combination of PLX2853 and Carboplatin | From time of first dose of PLX2853 and carboplatin until 30 days of end of treatment an average of 6 months. | MTD is defined as the maximum tolerated dose, which is determined from dose-limiting toxicity. If DLTs are observed in 2 or more of 6 subjects (or ≥33% of the cohort) at a dose level, the dose at which this occurs will be considered intolerable and the MTD will have been exceeded. The MTD is the dose below the intolerable dose. RP2D is the recommended Phase 2 dose, which was determined to be 80 mg |
| Phase 2a (PLX2853 + Carboplatin Combination): Number of Participants Reaching ORR as Measured by RECIST v1.1 | From 8 weeks of treatment with PLX2853 and Carboplatin (Cycle 3 Day 1; 28 days per cycle) until completion of long term follow-up, an average of 6 months. | Overall response rate as measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PLX2853 Phase 2a Monotherapy Up to 26 evaluable subjects with ARID1A mutation-positive advanced gynecological malignancies will be enrolled.
PLX2853: PLX2853 tablets | 14 |
| PLX2853 (40 mg) + Carboplatin Phase 1b Phase 1b (PLX2853 + carboplatin combination): Up to 15 evaluable subjects with platinum-resistant EOC will be enrolled.
PLX2853: PLX2853 tablets
Carboplatin: Carboplatin IV injection, 5 mg•min/mL | 3 |
| PLX2853 (80 mg) + Carboplatin Phase 1b Phase 1b (PLX2853 + carboplatin combination): Up to 15 evaluable subjects with platinum-resistant EOC will be enrolled.
PLX2853: PLX2853 tablets
Carboplatin: Carboplatin IV injection, 5 mg•min/mL | 7 |
| PLX2853 + Carboplatin Phase 2a Combination Therapy Phase 2a (PLX2853 + carboplatin combination): Up to 26 evaluable subjects with platinum-resistant EOC will be enrolled.
PLX2853: PLX2853 tablets
Carboplatin: Carboplatin IV injection, 5 mg•min/mL | 13 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 4 | 3 | 3 | 4 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Overall Study | Study discontinued early | 10 | 0 | 4 | 8 |
Baseline characteristics
| Characteristic | PLX2853 Phase 2a Monotherapy | PLX2853 (40 mg) + Carboplatin Phase 1b | PLX2853 (80 mg) + Carboplatin Phase 1b | PLX2853 + Carboplatin Phase 2a Combination Therapy | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 1 Participants | 3 Participants | 4 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 2 Participants | 4 Participants | 9 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 0 Participants | 11 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 3 Participants | 5 Participants | 0 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 11 Participants | 1 Participants | 4 Participants | 11 Participants | 27 Participants |
| Region of Enrollment Canada | 0 participants | 0 participants | 0 participants | 3 participants | 3 participants |
| Region of Enrollment United States | 14 participants | 0 participants | 7 participants | 10 participants | 34 participants |
| Sex: Female, Male Female | 14 Participants | 3 Participants | 7 Participants | 13 Participants | 37 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 14 | 11 / 23 |
| other Total, other adverse events | 14 / 14 | 20 / 23 |
| serious Total, serious adverse events | 6 / 14 | 10 / 23 |
Outcome results
Primary
Phase 1b (PLX2853 + Carboplatin Combination): Establish the Number of Participants Reaching MTD/RP2D for the Combination of PLX2853 and Carboplatin
MTD is defined as the maximum tolerated dose, which is determined from dose-limiting toxicity. If DLTs are observed in 2 or more of 6 subjects (or ≥33% of the cohort) at a dose level, the dose at which this occurs will be considered intolerable and the MTD will have been exceeded. The MTD is the dose below the intolerable dose. RP2D is the recommended Phase 2 dose, which was determined to be 80 mg
Time frame: From time of first dose of PLX2853 and carboplatin until 30 days of end of treatment an average of 6 months.
Population: Note that the MTD was not reached as the study terminated early.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PLX2853 Phase 2a Monotherapy | Phase 1b (PLX2853 + Carboplatin Combination): Establish the Number of Participants Reaching MTD/RP2D for the Combination of PLX2853 and Carboplatin | 0 Participants |
| PLX2853 + Carboplatin Phase 1b/2a Combination Therapy | Phase 1b (PLX2853 + Carboplatin Combination): Establish the Number of Participants Reaching MTD/RP2D for the Combination of PLX2853 and Carboplatin | 0 Participants |
Primary
Phase 2a (PLX2853 + Carboplatin Combination): Number of Participants Reaching ORR as Measured by RECIST v1.1
Overall response rate as measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Time frame: From 8 weeks of treatment with PLX2853 and Carboplatin (Cycle 3 Day 1; 28 days per cycle) until completion of long term follow-up, an average of 6 months.
Population: This outcome measure was not evaluated. The study was discontinued early and continued collection of disease status, which is required to determine overall response rate (ORR), was not conducted, therefore this measure is not reportable.
Primary
Phase 2a (PLX2853 Monotherapy): Number of Participants With Overall Response Rate (ORR) as Measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Overall response rate as measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Time frame: From 8 weeks of treatment for only PLX2853 (Cycle 3 Day 1; 28 days per cycle) until completion of long term follow-up, an average of 6 months.
Population: This outcome measure was not evaluated. The study was discontinued early and continued collection of disease status, which is required to determine overall response rate (ORR), was not conducted, therefore this measure is not reportable.