RP-6306 + Chemotherapy for Ovarian and Uterine Cancer

(GyneRep Trial)

Overseen By Stephanie Lheureux, MD

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: University Health Network, Toronto

Must be taking: Carboplatin, Paclitaxel

Must not be taking: Strong CYP3A inhibitors, inducers

Disqualifiers: Pregnancy, Uncontrolled infection, Cardiac diseases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 42

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 1 study to evaluate investigational drug RP-6306 in combination with carboplatin and paclitaxel in patients with TP53 mutated ovarian or uterine cancer. The dose escalation part of the study will determine the maximum tolerated dose (MTD) and recommended Phase 2 Dose (RP2D) and schedule of RP-6306 in combination with carboplatin and paclitaxel and the dose expansion will further assess the safety and tolerability as well as determine the preliminary efficacy of RP-6306 in combination with carboplatin and paclitaxel.

Do I need to stop my current medications to join the trial?

The trial requires that you stop taking chemotherapy or small molecule antineoplastic agents at least 21 days before starting the study treatment. Additionally, you should not be on strong CYP3A inhibitors or inducers within 14 days prior to the first dose. For other medications, the protocol does not specify, so it's best to discuss with the trial team.

What evidence supports the effectiveness of the drug combination RP-6306, carboplatin, and paclitaxel for ovarian and uterine cancer?

Research shows that combining paclitaxel and carboplatin is a standard and effective treatment for advanced ovarian cancer, with studies indicating significant activity and acceptable toxicity. Paclitaxel is particularly effective in patients resistant to platinum-based treatments, and the combination has been associated with improved quality of life. ^{1 2 3 4 5}

What safety information is available for the combination of RP-6306, carboplatin, and paclitaxel in treating ovarian and uterine cancer?

Carboplatin and paclitaxel have been studied for their safety in treating ovarian cancer, showing some risk of hypersensitivity reactions (allergic reactions) and blood-related side effects like neutropenia (low white blood cell count) and thrombocytopenia (low platelet count). The combination of albumin-bound paclitaxel (Abraxane) and carboplatin has a different safety profile, with a lower rate of severe neutropenia compared to solvent-based paclitaxel. ^{1 6 7 8 9}

What makes the drug RP-6306 combined with chemotherapy unique for treating ovarian and uterine cancer?

The combination of RP-6306 with carboplatin and paclitaxel is unique because it explores a novel agent (RP-6306) alongside standard chemotherapy drugs, potentially offering a new approach for patients who may not respond to traditional treatments. This trial aims to enhance the effectiveness of existing chemotherapy by integrating a new compound, which could provide additional benefits for patients with advanced ovarian and uterine cancers. ^{1 2 4 10 11}

Research Team

Stephanie Lheureux

Principal Investigator

The Princess Margaret Cancer Foundation

Eligibility Criteria

This trial is for women over 18 with advanced or recurrent ovarian and uterine cancer that's TP53 mutated, who can take oral meds, have good organ function, are not pregnant, and agree to use contraception. Excluded are those with recent major surgery, life-threatening conditions, uncontrolled infections like HIV/Hepatitis B/C, severe liver impairment or heart disease.

Inclusion Criteria

My ovarian or uterine cancer is advanced, cannot be cured with existing treatments.

I have tissue samples available for genetic testing.

My organs are functioning well enough for the study.

Exclusion Criteria

I haven't had chemotherapy or targeted cancer drugs within the last 3 weeks.

I don't have any health issues that could affect the study's results or my participation.

I am not allergic to RP-6306, carboplatin, or paclitaxel, or I can take them with steroids.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Determine the maximum tolerated dose (MTD) and recommended Phase 2 Dose (RP2D) of RP-6306 in combination with carboplatin and paclitaxel

21-day cycles

Visits every 21 days

Dose Expansion

Further assess the safety and tolerability and determine the preliminary efficacy of RP-6306 in combination with carboplatin and paclitaxel

21-day cycles

Visits every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Carboplatin
• Paclitaxel
• RP-6306

Trial Overview The study tests RP-6306 combined with carboplatin and paclitaxel in patients. It aims to find the safest dose (MTD) and see how well it works (efficacy). The first part sets the dose; the second part expands on safety data and preliminary effectiveness.

Participant Groups

Group I: Part B - Dose Expansion Experimental Treatment 3 Interventions

RP6306, 40 mg orally at the best schedule determined in Part A. Carboplatin, AUC 5 intravenously, on Day 1 of every 21-day cycle. Paclitaxel, 175 mg/m2 intravenously, on Day 1 every 21-day cycle.

Group II: Part A - Dose Escalation Experimental Treatment 3 Interventions

RP6306, 40 mg orally, twice a day, continuously or on Days 1 to 3, for 1 or 2 weeks, every 21-day cycle. Carboplatin, AUC 5 intravenously, on Day 1 of every 21-day cycle. Paclitaxel, 175 mg/m2 intravenously, on Day 1 of every 21-day cycle.

Carboplatin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Findings from Research

Cytoreductive surgery followed by platinum-based chemotherapy, particularly with carboplatin, remains the standard treatment for advanced epithelial ovarian cancer, but most patients are not cured, highlighting the need for improved therapies.

Paclitaxel, a novel agent effective in platinum-resistant ovarian cancer, is being tested in combination with platinum compounds in clinical trials for previously untreated patients, aiming to enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of ovarian cancer: current status. Ozols, RF.[2015]

In a study involving 247 patients with advanced ovarian cancer, both treatment regimens (standard carboplatin plus paclitaxel and alternating carboplatin/cisplatin plus paclitaxel) showed similar efficacy, with no significant differences in progression-free survival (PFS) or overall survival.

Both regimens were well tolerated, indicating that while the alternating regimen does not provide additional benefits, it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel plus carboplatin versus paclitaxel plus alternating carboplatin and cisplatin for initial treatment of advanced ovarian cancer: long-term efficacy results: a Hellenic Cooperative Oncology Group (HeCOG) study. Aravantinos, G., Fountzilas, G., Kosmidis, P., et al.[2022]

In a trial involving 59 women with advanced ovarian cancer, the combination of paclitaxel and carboplatin resulted in a high response rate of 72%, indicating effective treatment for this patient population.

Patients experienced significant improvements in quality of life during the outpatient treatment, with median survival times of 30.1 months for those with measurable disease, suggesting that this regimen is both effective and well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outpatient taxol and carboplatin chemotherapy for suboptimally debulked epithelial carcinoma of the ovary results in improved quality of life: an Eastern Cooperative Oncology Group Phase II Study (E2E93). Schink, JC., Weller, E., Harris, LS., et al.[2015]

The maximum tolerated doses (MTD) of ABI-007 in combination with carboplatin were determined to be 300 mg/m², 100 mg/m², and 125 mg/m² for three different treatment schedules, indicating a well-defined dosing strategy for future studies.

The combination therapy was well tolerated with a lower incidence of severe neutropenia compared to traditional solvent-based paclitaxel, showing promising activity against various solid tumors, including lung and breast cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic trial of carboplatin and albumin-bound paclitaxel, ABI-007 (Abraxane) on three treatment schedules in patients with solid tumors. Stinchcombe, TE., Socinski, MA., Walko, CM., et al.[2018]

In a study of 40 patients with ovarian, fallopian tube, or peritoneal cancers, the docetaxel/carboplatin regimen resulted in significantly higher rates of hematologic toxicity, with 80% of patients experiencing some form of it, including severe neutropenia in 45%.

Conversely, the paclitaxel/carboplatin group had a lower incidence of neutropenia and a higher occurrence of neuropathy, but both treatment regimens showed equivalent therapeutic efficacy, indicating that while side effects differ, the effectiveness in treating cancer remains similar.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel versus paclitaxel for adjuvant treatment of ovarian cancer: case-control analysis of toxicity. Hsu, Y., Sood, AK., Sorosky, JI.[2019]

In a study of 22 high-risk ovarian cancer patients treated with adjuvant paclitaxel and carboplatin, the treatment was generally well tolerated, with manageable side effects and a high completion rate of therapy (77% without delays).

The treatment led to significant clinical outcomes, with 16 out of 19 patients with advanced disease achieving complete clinical remission after six cycles, indicating strong efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and short-infusion paclitaxel in high-risk and advanced-stage ovarian carcinoma. Coleman, RL., Bagnell, KG., Townley, PM.[2015]

In a study of 62 patients with ovarian, fallopian tube, or primary peritoneal cancer, BRCA mutations did not significantly increase the likelihood of hypersensitivity reactions (HSRs) to carboplatin, with 30.8% of BRCA-mutated patients experiencing reactions compared to 44.9% of BRCA wild-type patients.

However, BRCA mutations were significantly associated with a lower incidence of HSRs to paclitaxel, where only 7.7% of BRCA-mutated patients had reactions compared to 53.1% of BRCA wild-type patients, indicating a potential protective effect of BRCA mutations against paclitaxel-related hypersensitivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence of Hypersensitivity Reactions to Carboplatin or Paclitaxel in Patients With Ovarian, Fallopian Tube, or Primary Peritoneal Cancer With or Without BRCA1 or BRCA2 Mutations. Garcia, A., Frahm, C., Jeter, JM., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Treatment of ovarian cancer: current status. [2015]

2. United States pubmed.ncbi.nlm.nih.gov

Taxane/platinum/anthracycline combination therapy in advanced epithelial ovarian cancer. [2015]

3. England pubmed.ncbi.nlm.nih.gov

Paclitaxel plus carboplatin versus paclitaxel plus alternating carboplatin and cisplatin for initial treatment of advanced ovarian cancer: long-term efficacy results: a Hellenic Cooperative Oncology Group (HeCOG) study. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Outpatient taxol and carboplatin chemotherapy for suboptimally debulked epithelial carcinoma of the ovary results in improved quality of life: an Eastern Cooperative Oncology Group Phase II Study (E2E93). [2015]

5. England pubmed.ncbi.nlm.nih.gov

Chemotherapy: Current drugs still have potential in advanced ovarian cancer. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic trial of carboplatin and albumin-bound paclitaxel, ABI-007 (Abraxane) on three treatment schedules in patients with solid tumors. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Docetaxel versus paclitaxel for adjuvant treatment of ovarian cancer: case-control analysis of toxicity. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Carboplatin and short-infusion paclitaxel in high-risk and advanced-stage ovarian carcinoma. [2015]

9. United States pubmed.ncbi.nlm.nih.gov

Incidence of Hypersensitivity Reactions to Carboplatin or Paclitaxel in Patients With Ovarian, Fallopian Tube, or Primary Peritoneal Cancer With or Without BRCA1 or BRCA2 Mutations. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Paclitaxel poliglumex and carboplatin as first-line therapy in ovarian, peritoneal or fallopian tube cancer: a phase I and feasibility trial of the Gynecologic Oncology Group. [2021]

11. England pubmed.ncbi.nlm.nih.gov

A phase I dose-finding study of a combination of pegylated liposomal doxorubicin (Doxil), carboplatin and paclitaxel in ovarian cancer. [2022]