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

18 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this phase I study is to test the safety of different dose levels of specially prepared cells collected called "modified T cells". In the screening part of this study the tumor was found to have a protein called MUC16. This protein is present on about 70% of ovarian cancers. The investigators want to find a safe dose of modified T cells for patients with this type of cancer that has progressed after standard chemotherapy. We also want to find out what effects these modified T cells have on the patient and their cancer.

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.

What data supports the effectiveness of the treatment Genetically Modified T Cells for Ovarian Cancer?

Research shows that genetically modified T cells, which are engineered to target specific cancer markers, have been effective in preclinical models of ovarian cancer by prolonging survival and reducing tumor growth. Additionally, combining these T cells with chemotherapy drugs like carboplatin has shown enhanced tumor regression in studies, suggesting potential benefits for patients with advanced ovarian cancer. ^{1 2 3 4 5}

Is the treatment with genetically modified T cells, including drugs like Cyclophosphamide and Fludarabine, generally safe for humans?

Research shows that Cyclophosphamide and Fludarabine have been used in various treatments, but they can have serious side effects like myelosuppression (a decrease in bone marrow activity leading to fewer blood cells). High doses of these drugs can lead to worse outcomes, so careful monitoring and dose adjustments are important for safety. ^{6 7 8 9 10}

How is the treatment with genetically modified T cells for ovarian cancer different from other treatments?

This treatment is unique because it uses genetically modified T cells, which are engineered to specifically recognize and attack ovarian cancer cells, offering a targeted approach compared to traditional chemotherapy or surgery. This method, known as CAR-T cell therapy, has shown promise in treating ovarian cancer by enhancing the body's immune response to the tumor. ^{1 3 5 11 12}

Research Team

Roisin O'Cearbhaill, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

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.

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

I have had one platinum-based and at least two other chemotherapy treatments for ovarian, peritoneal, or fallopian tube cancer.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Induction of Neoantigen-Specific Cytotoxic T Cells and Construction of T-cell Receptor-Engineered T Cells for Ovarian Cancer. [2022]

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

Engineered Adoptive T-cell Therapy Prolongs Survival in a Preclinical Model of Advanced-Stage Ovarian Cancer. [2023]

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

Synergistic Chemoimmunotherapy of Epithelial Ovarian Cancer Using ErbB-Retargeted T Cells Combined with Carboplatin. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Substantially modified ratios of effector to regulatory T cells during chemotherapy in ovarian cancer patients return to pre-treatment levels at completion: implications for immunotherapy. [2021]

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

Adoptive T cell immunotherapy strategies for the treatment of patients with ovarian cancer. [2022]

6. United States 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. [2021]

7. Canada pubmed.ncbi.nlm.nih.gov

High dose versus low dose fludarabine in the treatment of patients with severe refractory rheumatoid arthritis. [2013]

8. Germany pubmed.ncbi.nlm.nih.gov

Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Phase I study of fludarabine (2-fluoro-ara-AMP). [2019]

10. Germany pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration. [2021]

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

CAR-T cell therapy in ovarian cancer: from the bench to the bedside. [2019]

12. Germany 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. [2023]