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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of internal radiation therapy (brachytherapy) combined with two immune-boosting treatments, durvalumab or tremelimumab, for gynecological cancers that have resisted or returned after treatment. The study aims to determine which combination better stops cancer growth and spread. It seeks participants with ovarian, endometrial, or cervical cancer that hasn't responded well to previous treatments and who face challenges like cancer recurrence or spread. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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 there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have well-documented the safety of durvalumab, often used with other treatments like radiation. One study found no treatment-related deaths, indicating it can be safely administered. Another study involving durvalumab and a specific type of radiation therapy for cervical cancer showed promising safety results.

Tremelimumab, tested with radiation and durvalumab, showed few serious side effects in early trials. However, it did not significantly improve untreated tumors.

Both durvalumab and tremelimumab are types of immunotherapy that help the immune system fight cancer. While each has shown safety in trials, these treatments can have side effects, which researchers closely monitor during studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine brachytherapy with immunotherapy, offering a novel approach for recurrent gynecological cancer. Unlike standard treatments like chemotherapy, which directly target cancer cells, durvalumab and tremelimumab are immunotherapies that work by boosting the body's own immune system to fight cancer. This combination with brachytherapy, which delivers radiation directly to the tumor, could enhance the effectiveness of both therapies. This dual approach not only aims to improve outcomes but also potentially reduces side effects compared to more traditional cancer treatments.

What evidence suggests that this trial's treatments could be effective for recurrent gynecological cancer?

This trial will compare two treatment combinations for recurrent gynecological cancer. In one arm, participants will receive durvalumab alongside brachytherapy. Research has shown that durvalumab, when combined with certain radiation therapies, helps the immune system attack cancer cells more effectively. In the other arm, participants will receive tremelimumab with brachytherapy. Although less information exists on tremelimumab with brachytherapy, similar treatments suggest that combining immunotherapy with radiation can enhance the body's ability to fight cancer. Early results indicate these combinations could be effective, especially for cancers that don't respond to standard treatments. However, more research is needed to confirm these findings. ^{1 2 6 7 8}

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

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]

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]

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]

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]

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]

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]

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]

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]

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]

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. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8896055/

Phase Ib study of durvalumab (MEDI4736) in combination with ... Carbon-ion radiotherapy (CIRT) with the concurrent use of chemotherapy has shown promising results in such cases of difficult-to-treat uterine cervical cancer.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10342070/

A Phase Ib Study of Durvalumab (MEDI4736) in ... This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04395079

Study Details | NCT04395079 | Brachytherapy With ... This phase II trial studies the side effects and how well brachytherapy with durvalumab or tremelimumab work for the treatment of gynecological malignancies ...

4. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/46/NCT04003246/Prot_SAP_000.pdf

STU 2019-1082 Phase II Concurrent Durvalumab ( ... Despite aggressive therapy with concurrent chemoradiation, fewer than 20-25% of patients with stage III NSCLC achieve 5-year survival and are presumably cured.

5. researchgate.net researchgate.net/publication/371886465_A_Phase_Ib_Study_of_Durvalumab_MEDI4736_in_Combination_with_Carbon-Ion_Radiotherapy_and_Weekly_Cisplatin_for_Patients_with_Locally_Advanced_Cervical_Cancer_DECISION_Study_The_Early_Safety_and_Efficacy

(PDF) A Phase Ib Study of Durvalumab (MEDI4736) in ... All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04395079

Study Details | NCT04395079 | Brachytherapy With ... This trial is being done to see whether brachytherapy with durvalumab or tremelimumab works better in treating patients with gynecological malignancies.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.8536

A phase II study of durvalumab (MEDI4736) immediately ... There was no treatment-related death. Conclusions: Our study met the primary endpoint. Durvalumab can be safely administered immediately after ...

8. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03277482/

Clinical Trial: NCT03277482 This research study is evaluating the safety and effectiveness of 2 immunotherapy drugs in combination with radiation therapy as a possible ...