Heated Chemotherapy + Niraparib for Ovarian Cancer

(HOTT Trial)

Recruiting at 50 trial locations

Overseen By Jennifer Klein, MEd

Age: 18+

Sex: Female

Trial Phase: Phase 3

Sponsor: GOG Foundation

Must not be taking: Antibiotics, Antidiabetics, Antihypertensives, others

Disqualifiers: Low-grade serous, Myelodysplastic, Pregnancy, others

Stay on Your Current Meds You can continue your current medications while participating

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

230 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients will be registered prior to, during or at the completion of neoadjuvant chemotherapy (Paclitaxel 175 mg/m2 IV over 3 hours and Carboplatin AUC 6 IV on Day 1 every 21 days for 3-4 cycles). Registered patients who progress during neoadjuvant chemotherapy will not be eligible for iCRS and will be removed from the study. Following completion of neoadjuvant chemotherapy, interval cytoreductive surgery (iCRS) will be performed in the usual fashion in both arms. Patients will be randomized at the time of iCRS (iCRS must achieve no gross residual disease or no disease \>1.0 cm in largest diameter) to receive HIPEC or no HIPEC. Patients randomized to HIPEC (Arm A) will receive a single dose of cisplatin (100mg/m2 IP over 90 minutes at 42 C) as HIPEC. After postoperative recovery patients will receive standard post-operative platinum-based combination chemotherapy. Patients randomized to surgery only (Arm B) will receive postoperative standard chemotherapy after recovery from surgery. Both groups will receive an additional 2-3 cycles of platinum-based combination chemotherapy per institutional standard (Paclitaxel 175 mg/m2 IV over 3 hours and Carboplatin AUC 6 IV on Day 1 every 21 days for 2-3 cycles) for a maximum total of 6 cycles of chemotherapy (neoadjuvant plus post-operative cycles) followed by niraparib individualized dosing until progression or 36 months (if no evidence of disease).

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, patients on stable doses of corticosteroids for at least 4 weeks prior to randomization can continue them, and those with controlled HIV can continue antiretroviral therapy. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Niraparib for ovarian cancer?

Niraparib has been shown to significantly extend the time patients live without their cancer getting worse (progression-free survival) in several studies, including a large phase III trial. It is effective for patients with ovarian cancer who have responded to platinum-based chemotherapy, regardless of specific genetic mutations. ^{1 2 3 4 5}

Is the combination of heated chemotherapy and Niraparib safe for treating ovarian cancer?

Cisplatin, a component of heated chemotherapy, has been used in ovarian cancer treatment and can cause side effects like neuropathy (nerve damage) and blood-related issues such as neutropenia (low white blood cell count) and thrombocytopenia (low platelet count). Niraparib, another component, is generally well-tolerated but can also cause blood-related side effects. While these treatments have been used safely in many patients, they can have serious side effects, and their safety should be discussed with a healthcare provider. ^{6 7 8 9 10}

How does the treatment of heated chemotherapy combined with niraparib differ from other ovarian cancer treatments?

This treatment is unique because it combines heated chemotherapy, which may enhance the effectiveness of the drugs by increasing their absorption, with niraparib, a PARP inhibitor that helps prevent cancer cells from repairing themselves. Niraparib is already used as a maintenance therapy for ovarian cancer, but combining it with heated chemotherapy could potentially offer a new approach to improve outcomes. ^{2 3 4 11 12}

Research Team

Oliver Zivanovic, MD

Principal Investigator

GOG Foundation

Eligibility Criteria

This trial is for patients with advanced high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer. They must have completed neoadjuvant chemotherapy and be candidates for surgery without large remaining tumors. Participants need normal organ function tests and a specific genetic test result before joining.

Inclusion Criteria

I am older than 18 years.

Patients must have a life expectancy > 3 months

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

I have an active liver or biliary disease.

Patients with other uncontrolled, inter-current medical conditions

My ovarian cancer is of a specific type (low-grade serous, clear cell, mucinous, or non-epithelial).

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Chemotherapy

Participants receive Paclitaxel and Carboplatin every 21 days for 3-4 cycles

9-12 weeks

Interval Cytoreductive Surgery (iCRS)

Surgery performed to achieve no gross residual disease, followed by randomization to HIPEC or no HIPEC

1 week

Post-operative Chemotherapy

Participants receive additional 2-3 cycles of platinum-based combination chemotherapy

6-9 weeks

Niraparib Maintenance

Participants receive niraparib individualized dosing until progression or 36 months

Up to 36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 8 years

Treatment Details

Interventions

• Cisplatin
• Niraparib

Trial Overview The study compares two approaches after initial chemo: one group receives heated intraperitoneal chemotherapy (HIPEC) with cisplatin during surgery, while the other does not. Both groups get more chemo post-surgery and then niraparib until disease progression or up to 36 months.

Participant Groups

Group I: HIPEC Experimental Treatment 1 Intervention

Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Cisplatin 100 mg/m2 IP over 90 minutes at 42 degrees C

Group II: No HIPEC Active Control 1 Intervention

No treatment

Who Is Running the Clinical Trial?

GOG Foundation

Lead Sponsor

Trials

48

Recruited

18,500+

GlaxoSmithKline

Industry Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Findings from Research

Niraparib, a PARP inhibitor, has shown significant efficacy in improving progression-free survival in women with platinum-sensitive recurrent high-grade serous ovarian cancer (HGSOC) after chemotherapy, with the greatest benefits observed in those with BRCA1/2 mutations.

The Myriad MyChoice HRD test may help identify patients who could benefit from niraparib, as even those without BRCA mutations may still respond positively, indicating its potential use in broader patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib for the treatment of ovarian cancer. Kanjanapan, Y., Lheureux, S., Oza, AM.[2018]

Niraparib, a recently approved treatment for recurrent platinum-sensitive ovarian cancer, has demonstrated a high oral bioavailability of 72.7% in humans, indicating effective absorption when taken orally.

The study involved six patients who received a therapeutic dose of 300 mg of niraparib, followed by a small intravenous dose to measure its levels in the bloodstream, confirming its potential as a convenient oral treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients. van Andel, L., Rosing, H., Zhang, Z., et al.[2019]

Niraparib significantly extends progression-free survival in patients with newly diagnosed advanced ovarian cancer, showing efficacy in both homologous-recombination deficiency positive (HRd) and negative (HRp) populations, based on a phase III trial.

The treatment has a manageable safety profile, with myelosuppression as the main concern, which can be effectively managed through monitoring and individualized dosing based on weight and platelet count.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer. Lee, A.[2022]

Niraparib significantly improves progression-free survival and other key outcomes in patients with recurrent, platinum-sensitive ovarian cancer, based on the phase III NOVA trial involving a randomized, double-blind, placebo-controlled design.

The treatment has a manageable safety profile, with most serious side effects being blood-related issues, which can be effectively managed through dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in Ovarian Cancer. Heo, YA., Duggan, ST.[2019]

Niraparib, a PARP inhibitor, is recommended as a maintenance treatment for patients with platinum-sensitive relapsed ovarian cancer, leveraging the concept of synthetic lethality in BRCA mutation carriers.

A case study of a 68-year-old woman with brain metastases from high-grade serous ovarian cancer showed that she remained free of disease progression for over 17 months while on niraparib after second-line chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib as maintenance therapy in a patient with ovarian cancer and brain metastases. Gray, S., Khor, XY., Yiannakis, D.[2021]

In a study involving 25 ovarian cancer patients who had previously been treated with platinum-based therapies, the combination of oxaliplatin and cisplatin showed an overall objective response rate of 40%, with 8% achieving complete responses and 32% partial responses.

The main side effect of this treatment was cumulative sensory peripheral neuropathy, which was severe in some cases but reversible after stopping the treatment, highlighting the need for careful monitoring of patients during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxaliplatin/cisplatin (L-OHP/CDDP) combination in heavily pretreated ovarian cancer. Soulié, P., Bensmaïne, A., Garrino, C., et al.[2019]

Intraperitoneal carboplatin (IP-Ca) treatment in 31 ovarian cancer patients with minimal residual disease after chemotherapy showed promising results, with 2 patients achieving a complete pathological response lasting over 33 months.

The maximum tolerable dose of IP-Ca was determined to be 300 mg/m2, with thrombocytopenia being the main dose-limiting toxicity, affecting 27% of patients at the highest dose, while side effects were generally mild.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraperitoneal carboplatin in the treatment of minimal residual ovarian cancer. Pfeiffer, P., Bennedbaek, O., Bertelsen, K.[2019]

The combination of paclitaxel and carboplatin showed an overall response rate of 42% in 73 patients with advanced ovarian cancer who had previously undergone platinum-based chemotherapy, indicating its efficacy as a treatment option.

While myelosuppression was the most common severe side effect, with significant rates of neutropenia, the therapy was generally well-tolerated, with only one case of febrile neutropenia and manageable levels of other toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of the paclitaxel and carboplatin combination in patients with previously treated advanced ovarian carcinoma. A multicenter GINECO (Group d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens) phase II study. Guastalla, JP., Pujade-Lauraine, E., Weber, B., et al.[2020]

In a study of 32 patients with small-volume platinum-sensitive epithelial ovarian cancer, the combination of intraperitoneal (IP) cisplatin and intravenous (IV) paclitaxel showed a median progression-free interval of 13 months and a median overall survival of 27 months, indicating some efficacy in this patient population.

However, the treatment was associated with significant neurotoxicity, leading to dose interruptions in 21.9% of patients, and the authors concluded that this regimen is not recommended for routine use in treating persistent peritoneal cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraperitoneal cisplatin and intravenous paclitaxel in the treatment of epithelial ovarian cancer patients with a positive second look. Makhija, S., Sabbatini, P., Aghajanian, C., et al.[2015]

In a study of 735 women treated with carboplatin for gynecological cancers, 10.2% experienced hypersensitivity reactions, with the incidence increasing significantly over the years from 0.88% in 2006 to 5.42% in 2013.

Risk factors for these reactions included advanced disease stage, specific cancer histologies, presence of malignant ascites, and a history of other drug allergies, suggesting that careful monitoring and potential preventive measures, like adjusting infusion rates and using desensitization protocols, could help manage these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk Factors of Hypersensitivity to Carboplatin in Patients with Gynecologic Malignancies. Tai, YH., Tai, YJ., Hsu, HC., et al.[2020]

New maintenance therapies, particularly poly-(ADP-ribose) polymerase inhibitors (PARPi), have significantly improved the prognosis for patients with advanced ovarian cancer, especially those with BRCA1 or BRCA2 mutations.

The standard treatment for advanced ovarian cancer includes a combination of carboplatin and paclitaxel, with the option of adding bevacizumab, while PARPi can be used as maintenance therapy after achieving a response to chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Évolution des traitements adjuvants des cancers de l'ovaire]. Pautier, P.[2022]

Niraparib, a PARP inhibitor, has been shown to be safe for long-term use in patients with recurrent ovarian cancer, with a significant reduction in treatment-emergent adverse events (TEAEs) over time, particularly in the first month of treatment.

The study highlighted the importance of dose adjustments, as the incidence of severe side effects like thrombocytopenia decreased significantly after the initial month, indicating that careful management can enhance the safety of niraparib therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo: Results from the phase III ENGOT-OV16/NOVA trial. Mirza, MR., Benigno, B., Dørum, A., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Niraparib for the treatment of ovarian cancer. [2018]

2. Germany pubmed.ncbi.nlm.nih.gov

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients. [2019]

3. France pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer. [2022]

4. France pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in Ovarian Cancer. [2019]

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

Niraparib as maintenance therapy in a patient with ovarian cancer and brain metastases. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Oxaliplatin/cisplatin (L-OHP/CDDP) combination in heavily pretreated ovarian cancer. [2019]

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

Intraperitoneal carboplatin in the treatment of minimal residual ovarian cancer. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of the paclitaxel and carboplatin combination in patients with previously treated advanced ovarian carcinoma. A multicenter GINECO (Group d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens) phase II study. [2020]

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

Intraperitoneal cisplatin and intravenous paclitaxel in the treatment of epithelial ovarian cancer patients with a positive second look. [2015]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Risk Factors of Hypersensitivity to Carboplatin in Patients with Gynecologic Malignancies. [2020]

11. France pubmed.ncbi.nlm.nih.gov

[Évolution des traitements adjuvants des cancers de l'ovaire]. [2022]

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

Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo: Results from the phase III ENGOT-OV16/NOVA trial. [2021]