Genetically Modified T Cells for Ovarian Cancer

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Immunotherapy, Corticosteroids

Disqualifiers: Hepatitis, HIV, Autoimmune, Heart disease, others

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

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of genetically modified T cells for treating ovarian cancer that has returned after standard chemotherapy. Researchers aim to determine a safe dose of these modified T cells and assess their effects on the cancer and the patient. The treatment process involves administering drugs like cyclophosphamide and fludarabine before introducing the modified T cells. Candidates for the trial typically have high-grade ovarian cancer that has recurred, particularly if their cancer expresses a specific protein (MUC16) targeted by these T cells. As a Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial requires that you stop any anti-cancer therapy, including chemotherapy, biologic therapy, or immunotherapy, at least 3 weeks before the T cell infusion. Hormonal therapy must be stopped at least one week prior, but hormone replacement therapy can continue.

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

Research has shown that treatments like genetically modified T cells are generally well-tolerated by patients. These T cells are specially designed to find and attack cancer cells, and studies have demonstrated they usually cause only mild side effects. Patients might experience some discomfort, but it is often not severe.

When combined with the chemotherapy drugs cyclophosphamide and fludarabine, the plan aims to reduce side effects and improve effectiveness. Cyclophosphamide, a well-known chemotherapy drug, helps prepare the body to receive the T cells. Fludarabine, another chemotherapy drug, also aids in this process.

Overall, earlier studies have used the engineered T cells and these chemotherapy drugs, and they are considered safe enough for further testing. This is an early-phase trial, so while the main goal is to find a safe dose, existing research suggests a promising safety profile. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about genetically modified T cells for ovarian cancer because they offer a unique and targeted approach. Unlike standard treatments like surgery, chemotherapy, and radiation, which broadly attack cancer cells, these T cells are engineered to specifically recognize and destroy cancer cells. This precise targeting could lead to increased effectiveness and potentially fewer side effects. Additionally, the use of genetic modification allows these T cells to be more powerful and persistent in fighting the cancer, offering hope for better outcomes in patients with this challenging condition.

What evidence suggests that genetically modified T cells could be an effective treatment for ovarian cancer?

Research has shown that a new treatment using genetically modified T cells, called immunotherapy, could help treat ovarian cancer. In this trial, participants will receive Cyclophosphamide followed by an infusion of these specially designed T cells. These T cells are engineered to attack certain proteins, like MUC16, present in about 70% of ovarian cancer cases. Similar technology, known as CAR-T cell therapy, has successfully treated some solid tumors, including ovarian cancer. Early studies showed positive results, indicating that these modified T cells might help patients who haven't responded to standard treatments. While more research is needed, the initial findings are promising. ^{5 6 7 8 9}

Who Is on the Research Team?

Roisin O'Cearbhaill, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with high-grade serous ovarian, primary peritoneal, or fallopian tube carcinoma that has recurred. They must have measurable disease, a life expectancy of over 3 months, and no recent cancer treatments. Their tumors should express MUC16ecto antigen and they've had at least one platinum-based chemotherapy. Exclusions include bowel obstruction, autoimmune diseases (except stable thyroid), brain metastases, seizure history, significant heart conditions, active infections like hepatitis B/C or HIV.

Inclusion Criteria

You are expected to live for at least 3 more months.

I am able to care for myself but cannot do normal activities or work.

My cancer has returned and can be measured for its size.

Exclusion Criteria

I have cancer that has spread to my brain or its coverings.

I have serious heart conditions, including recent heart attack or severe heart failure.

I have stable brain metastases and am not currently on steroids.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

1 visit (in-person)

Intervention

Preparation and infusion of genetically-modified T cells, including conditioning chemotherapy with cyclophosphamide and fludarabine

4-6 weeks for T cell preparation, followed by infusion

Multiple visits for chemotherapy and T cell infusions

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days for initial safety assessment, up to 2 years for long-term follow-up

Regular visits for monitoring

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Fludarabine
• Genetically-modified T cells

Trial Overview The study tests the safety of different doses of modified T cells targeting the MUC16 protein on certain solid tumors. It involves collecting patients' T cells and genetically modifying them to attack tumor cells before being infused back into the patient's body along with pre-treatment drugs Cyclophosphamide and Fludarabine.

How Is the Trial Designed?

Group I: Cyclophosphamide followed by Autologous T Cells Experimental Treatment 5 Interventions

Cohorts of 3-6 pts will be infused with escalating doses of modified T cells to establish the MTD of modified T cells. There are 5 planned dose levels: 3 x 10\^5, 1 x 10\^6, 3 x 10\^6, \& 1 x 10\^7 \& 3 x 10\^7 4H11-28z/fIL-12/EGFRt+ T cells/kg. Cohort I-IV \& VI will be treated escalating dose levels. Once the MTD of T cells is established, the next cohort will receive lymphodepleting cyclophosphamide dose of 750 mg/m\^2 or a regimen of cyclophosphamide dose 300 mg/m2 x 3 days concurrent with fludarabine dose 25-30 mg/m2 x 3 days 2-7 days prior to starting the T cell infusion at one dose level below the MTD. If MTD isn't established after Cohort IV, Cohort V will receive conditioning chemotherapy 2-7 days prior to starting the T cell infusion at the same dose as Cohort III. Pts in Cohort V received cyclophosphamide chemotherapy on Day 1 or cyclophosphamide concurrent with fludarabine on Day 1-3, followed 2 to 4 days later by T cell infusion. This cohort is closed to further accrual.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Stanford University

Collaborator

Trials

2,527

Recruited

17,430,000+

Juno Therapeutics, Inc., a Bristol-Myers Squibb Company

Industry Sponsor

Trials

19

Recruited

3,100+

Juno Therapeutics, Inc.

Industry Sponsor

Trials

8

Recruited

810+

Published Research Related to This Trial

Chimeric antigen receptor-modified T (CAR-T) cell therapy shows promising clinical efficacy in treating ovarian cancer, as supported by various preclinical experiments and clinical trials.

While CAR-T therapy offers a novel approach to cancer treatment, it is associated with side effects and toxicities, including cytokine release syndrome and 'on-target, off-tumor' effects, which need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T cell therapy in ovarian cancer: from the bench to the bedside. Zhu, X., Cai, H., Zhao, L., et al.[2019]

In a study of 102 patients undergoing hematopoietic cell transplantation (HCT) with fludarabine and low-dose total body irradiation, significant variability was observed in pharmacological biomarkers related to fludarabine metabolism, indicating that individual responses to the drug can differ widely.

Despite the variability in biomarkers such as F-ara-A area under the curve and F-ara-ATP accumulation, no significant associations were found between these biomarkers and clinical outcomes like acute graft-versus-host disease or overall mortality, suggesting that these pharmacological measures may not predict treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. McCune, JS., Mager, DE., Bemer, MJ., et al.[2018]

Adoptive transfer of genetically modified T cells, specifically those expressing chimeric antigen receptors (CARs), shows promise as a novel treatment for ovarian cancer, which is known for its poor prognosis after standard therapies.

Ovarian tumors are relatively immunogenic, meaning they can provoke a natural immune response, making them suitable candidates for T cell immunotherapy, which is currently being explored in both pre-clinical and clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive T cell immunotherapy strategies for the treatment of patients with ovarian cancer. Chekmasova, AA., Brentjens, RJ.[2022]

Fludarabine phosphate, an antimetabolite derived from adenosine arabinoside, has been found to be safe at a dose of 20 mg/m2 administered every 12 hours for 6 doses in good-risk patients during a phase I trial.

The main side effect of fludarabine phosphate is myelosuppression, which can become severe at higher doses, highlighting the need for careful dose management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of fludarabine (2-fluoro-ara-AMP). Kavanagh, JJ., Krakoff, IH., Bodey, GP.[2019]

The study successfully developed a rapid 2-week protocol to create neoantigen-specific TCR-engineered T cells from ovarian cancer patients, demonstrating the feasibility of this approach for advanced cancers.

While the engineered T cells showed effective cytotoxic activity against neoantigens, one case exhibited cross-reactivity with a wild-type peptide, highlighting the need for careful validation to prevent potential immune-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of Neoantigen-Specific Cytotoxic T Cells and Construction of T-cell Receptor-Engineered T Cells for Ovarian Cancer. Matsuda, T., Leisegang, M., Park, JH., et al.[2022]

A population pharmacokinetic/pharmacodynamic model was developed using data from 41 hematopoietic cell transplant recipients to understand how different concentrations of F-ara-A affect lymphocyte suppression.

The model successfully characterized the variability in absolute lymphocyte counts during treatment, indicating that the specific HCT protocol significantly influenced lymphocyte kill rates and could help optimize future fludarabine-based conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration. McCune, JS., Vicini, P., Salinger, DH., et al.[2021]

Engineered CAR T cells targeting both Muc16 and WT1 antigens in ovarian cancer show enhanced anticancer activity, especially against tumors with low Muc16 expression, indicating a promising approach to overcome treatment resistance.

The use of a bispecific T cell engager (BiTE) allows these CAR T cells to recruit additional T cells to attack cancer cells, enhancing the overall effectiveness of the therapy in both laboratory and mouse models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual targeting ovarian cancer by Muc16 CAR T cells secreting a bispecific T cell engager antibody for an intracellular tumor antigen WT1. Mun, SS., Meyerberg, J., Peraro, L., et al.[2023]

In a study of 89 hematopoietic cell transplantation recipients, higher levels of the active metabolite of cyclophosphamide (PM AUC0-8 hr) were linked to worse nonrelapse mortality and overall survival, indicating that careful monitoring of this metabolite is crucial for patient outcomes.

Patients with low levels of the active metabolite of fludarabine (F-ara-ADay-4) and low PM AUC0-8 hr had significantly lower nonrelapse mortality, suggesting that optimizing drug exposure could improve safety and efficacy in reduced-intensity conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy. Takahashi, T., Scheibner, A., Cao, Q., et al.[2021]

Citations

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CAR-T Cell Therapy in Ovarian Cancer: Where Are We Now? Among immunotherapies, chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated exceptional results in hematologic malignancies with six FDA-approved ...

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CAR-T cell therapy for cancer: current challenges and ... 2-targeted CAR has proven effective in treating gastrointestinal tumors in a study including 37 patients (NCT04196413), with an overall response ...

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Overcoming ovarian cancer resistance and evasion to CAR ... The findings suggest that AlloCAR-NKT cells offer a safer, more effective, and readily available immunotherapy for patients with ovarian cancer. Summary ...

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NCT05225363 | Modified Immune Cells (TAG72-CAR T ... This phase I trial tests the safety, side effects, and best dose of TAG72-chimeric antigen receptor (CAR) T cells in treating patients with epithelial ...

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CAR T Cells: Engineering Immune Cells to Treat Cancer Positive results have also been seen in small clinical trials testing CAR T-cell therapies in people with other solid cancers, including ovarian ...

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Safety Strategies of Genetically Engineered T Cells in ... Equipped with powerful tools such as sophisticated synthetic biology and genetic engineering techniques, we expect an improved safety profile, enhanced potency ...

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Adoptive T cell therapy for ovarian cancer published trial results of lymphodepletion followed by TIL therapy for ovarian cancer treatment. A 71% objective response rate was reported with one complete ...

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CAR-T cell immunotherapy for ovarian cancer Overall, such studies can conclude that TCR-engineered T cells with antigen-specific TCRs are well-tolerated in patients and can mediate mild therapeutic ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT05225363

NCT05225363 | Modified Immune Cells (TAG72-CAR T ... This phase I trial tests the safety, side effects, and best dose of TAG72-chimeric antigen receptor (CAR) T cells in treating patients with epithelial ovarian ...