Brachytherapy + Immunotherapy for Recurrent Gynecological Cancer

Overseen By Vincent Basehart

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Jonsson Comprehensive Cancer Center

Must not be taking: Immunosuppressants, others

Disqualifiers: Autoimmune disorders, Brain metastases, others

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

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 12 months

9 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase II trial studies the side effects and how well brachytherapy with durvalumab or tremelimumab work for the treatment of gynecological malignancies that is resistant to platinum therapy (platinum-resistant), does not respond to treatment (refractory), has come back (recurrent), or has spread to other places in body (metastatic). Brachytherapy, also known as internal radiation therapy, uses radioactive material placed directly into or near a tumor to kill tumor cells. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This trial is being done to see whether brachytherapy with durvalumab or tremelimumab works better in treating patients with gynecological malignancies.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on any concurrent cancer treatments, and there is a required washout period (time without taking certain medications) of at least 21 days for previous anticancer therapies before starting the study drug.

Is the combination of durvalumab and tremelimumab generally safe for humans?

The combination of durvalumab and tremelimumab has been studied in various cancers, showing that serious side effects can occur, such as reduced appetite and diarrhea. In one study, 63.6% of patients experienced severe side effects, mostly related to chemotherapy, but the combination's safety profile was considered expected. ^{1 2 3 4 5}

How is the treatment of brachytherapy combined with durvalumab and tremelimumab unique for recurrent gynecological cancer?

This treatment is unique because it combines brachytherapy (a type of internal radiation therapy) with two immunotherapy drugs, durvalumab and tremelimumab, which work by enhancing the body's immune response to fight cancer cells. This combination aims to improve outcomes by using both radiation and immune system activation, which is different from traditional chemotherapy or radiation alone. ^{5 6 7 8 9}

What data supports the effectiveness of the drug combination of durvalumab and tremelimumab for treating recurrent gynecological cancer?

The combination of durvalumab and tremelimumab has shown effectiveness in improving survival in other cancers, such as non-small cell lung cancer and hepatocellular carcinoma, when used with chemotherapy. This suggests potential benefits for recurrent gynecological cancer, although direct evidence for this specific condition is not yet available. ^{2 5 6 7 10}

Who Is on the Research Team?

Albert Chang, MD

Principal Investigator

UCLA / Jonsson Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for women with certain gynecological cancers (like ovarian, endometrial, or cervical) that haven't responded to platinum therapy and may have spread. Participants should be in good enough health to undergo internal radiation, not pregnant, able to consent, and without serious infections like TB or hepatitis. They shouldn't have used checkpoint inhibitors before or had recent major surgery.

Inclusion Criteria

Absolute neutrophil count (ANC) >= 1.5 (or 1.0) x (>= 1500 per mm^3)

Hemoglobin >= 9.0 g/dL

Subjects must consent to provide an archived tumor specimen from within 12 months prior to study entry

Exclusion Criteria

I have received an organ transplant from another person.

I've had radiation where the treatment area overlaps with where they plan to do brachytherapy.

I have previously used checkpoint inhibitors.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive durvalumab or tremelimumab intravenously, followed by brachytherapy. Durvalumab is administered every 28 days for up to 13 cycles, and tremelimumab for 2-4 cycles. Brachytherapy is administered every 21 days for 3 fractions.

Up to 12 months

Multiple visits for IV administration and brachytherapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab
• Internal Radiation Therapy
• Tremelimumab

Trial Overview The study tests brachytherapy combined with the immune-boosting drugs Durvalumab or Tremelimumab on gynecological cancers resistant to standard treatments. It aims to see if placing radioactive material near tumors plus immunotherapy can effectively kill cancer cells and prevent growth.

How Is the Trial Designed?

Group I: Arm II (tremelimumab, brachytherapy) Experimental Treatment 2 Interventions

Patients receive tremelimumab IV on day 1. Treatment repeats every 28 days for 2-4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo brachytherapy on day 8. Treatment repeats every 21 days for 3 fractions in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (durvalumab, brachytherapy) Experimental Treatment 2 Interventions

Patients receive durvalumab IV on day 1. Treatment repeats every 28 days for 13 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo brachytherapy on day 8. Treatment repeats every 21 days for 3 fractions in the absence of disease progression or unacceptable toxicity.

Durvalumab is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)

Approved in United States as Imfinzi for:

• Extensive-stage small cell lung cancer (ES-SCLC)
• Limited-stage small cell lung cancer (LS-SCLC)
• Locally advanced or metastatic urothelial carcinoma

Approved in Japan as Imfinzi for:

• Not specified in provided sources

Who Is Running the Clinical Trial?

Jonsson Comprehensive Cancer Center

Lead Sponsor

Trials

373

Recruited

35,200+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

This phase II study aims to evaluate the effectiveness of combining durvalumab and tremelimumab with neoadjuvant chemotherapy in improving progression-free survival (PFS) in patients with advanced-stage ovarian cancer, specifically those with stage IIIC/IV epithelial ovarian cancer.

The study will involve 24 patients and will assess immune biomarkers and changes in the tumor microenvironment through serial biopsies, with the primary goal of achieving a 12-month PFS rate, while also monitoring safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of neoadjuvant chemotherapy plus durvalumab and tremelimumab in advanced-stage ovarian cancer: a Korean Gynecologic Oncology Group Study (KGOG 3046), TRU-D. Lee, JY., Kim, JW., Lim, MC., et al.[2020]

Tremelimumab shows linear pharmacokinetics with a two-compartment model, and its clearance varies depending on whether it is used as monotherapy or in combination with durvalumab, with a 16% increase in clearance for monotherapy and a 17% decrease for combination therapy over one year.

Factors like higher body weight and lower albumin levels lead to higher drug clearance, but no dosage adjustments are needed, as a flat dose of 75 mg provides similar exposure to the weight-based dosing of 1 mg/kg in adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic modelling of tremelimumab in patients with advanced solid tumours and the impact of disease status on time-varying clearance. Hwang, M., Chia, YL., Zheng, Y., et al.[2023]

Durvalumab is an FDA-approved monoclonal antibody that enhances T-cell responses against cancer by blocking the PD-L1 pathway, specifically for patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy.

The drug is currently being tested in phase III trials for various cancers, including lung and head and neck cancers, indicating its potential broad application in oncology beyond urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. Syed, YY.[2022]

In the phase 3 POSEIDON study involving 1013 treatment-naïve patients with metastatic non-small-cell lung cancer (NSCLC), the combination of tremelimumab, durvalumab, and chemotherapy significantly improved overall survival and progression-free survival compared to chemotherapy alone.

Patients receiving the combination treatment also experienced a longer time to deterioration in quality of life and various symptoms, indicating better overall health status compared to those on chemotherapy, supporting its use as a first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON). Garon, EB., Cho, BC., Luft, A., et al.[2023]

Tremelimumab, a CTLA-4 blocking antibody, was approved in the USA in October 2022 for treating unresectable hepatocellular carcinoma (uHCC) in combination with durvalumab, marking a significant advancement in cancer therapy.

In November 2022, tremelimumab was also approved for metastatic non-small cell lung cancer (mNSCLC) when combined with durvalumab and platinum-based chemotherapy, indicating its broad potential in treating various malignant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tremelimumab: First Approval. Keam, SJ.[2023]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

In a safety run-in phase of the DURIGAST PRODIGE 59 study involving 11 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, 63.6% experienced significant adverse events, primarily neutropenia, indicating a notable safety concern with the treatment combination.

The combination of FOLFIRI with Durvalumab and/or Tremelimumab showed an expected safety profile, allowing progression to the randomized phase II study, although careful monitoring for serious adverse events is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. Evrard, C., Aparicio, T., Soularue, E., et al.[2022]

Patients with metastatic non-small-cell lung cancer who developed immune-mediated adverse events (imAEs) while treated with durvalumab showed significantly improved overall survival compared to those without imAEs, indicating a potential link between imAE development and treatment efficacy.

A predictive model was created using machine learning to identify patients at higher risk of developing imAEs, which could help tailor treatment strategies and enhance patient outcomes in immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between immune-mediated adverse events and efficacy in metastatic non-small-cell lung cancer patients treated with durvalumab and tremelimumab. Dey, A., Austin, M., Kluger, HM., et al.[2022]

Tremelimumab is a fully human IgG2 antibody targeting CTLA4, currently in phase III trials for malignant melanoma and phase II trials for several other cancers, indicating its broad potential in cancer treatment.

The drug is being investigated for multiple cancer types, including colorectal, gastrointestinal, gynecological, non-small cell lung, prostate, breast, and pancreatic cancers, showcasing its versatility in oncology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tremelimumab. [2023]

The combination of durvalumab and tremelimumab was studied in 19 articles involving 2052 patients with solid tumors, showing some benefits over traditional chemotherapy in certain tumor types.

However, this combination did not consistently outperform durvalumab alone, indicating that while it may have potential, further research with larger and better-designed studies is needed to clarify its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab Plus Tremelimumab in Solid Tumors: A Systematic Review. Arru, C., De Miglio, MR., Cossu, A., et al.[2023]

Citations

1. Korea (South) pubmed.ncbi.nlm.nih.gov

A phase II study of neoadjuvant chemotherapy plus durvalumab and tremelimumab in advanced-stage ovarian cancer: a Korean Gynecologic Oncology Group Study (KGOG 3046), TRU-D. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic modelling of tremelimumab in patients with advanced solid tumours and the impact of disease status on time-varying clearance. [2023]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. [2022]

4. Ireland pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON). [2023]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Tremelimumab: First Approval. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Association between immune-mediated adverse events and efficacy in metastatic non-small-cell lung cancer patients treated with durvalumab and tremelimumab. [2022]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Tremelimumab. [2023]

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

Durvalumab Plus Tremelimumab in Solid Tumors: A Systematic Review. [2023]