Autologous T Cells With or Without Cyclophosphamide and Fludarabine in Treating Patients With Recurrent or Persistent Advanced Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer (Fludarabine Treatment Closed as of 12/01/2009)

NCT00562640CompletedPHASE1INTERVENTIONAL

Summary

RATIONALE: Giving colony-stimulating factors, such as G-CSF, helps stem cells move from the bone marrow to the blood so they can be collected. Treating stem cells collected from the patient's blood in the laboratory may increase the number of immune cells that can mount an immune response against the tumor. The treated stem cells may help destroy any remaining tumor cells (graft-versus-tumor effect). Chemotherapy may also be given to the patient to prepare the bone marrow for the stem cell transplant. PURPOSE: This phase I trial is studying the side effects and best dose of autologous T cells when given with or without cyclophosphamide and fludarabine in treating patients with recurrent or persistent advanced ovarian epithelial cancer, primary peritoneal cavity cancer, or fallopian tube cancer. (fludarabine treatment closed as of 12/012009)

Key Facts

Lead Sponsor

Memorial Sloan Kettering Cancer Center

Enrollment

12

Start Date

2007-10-16

Completion Date

2021-08-03

Study Type

INTERVENTIONAL

Official Title

A Phase I Dose Escalation Safety and Feasibility Study of WT1-Specific T Cells for the Treatment of Patients With Advanced Ovarian, Primary Peritoneal, and Fallopian Tube Carcinomas

Interventions

filgrastimtherapeutic autologous lymphocytescyclophosphamidelaboratory biomarker analysis

Conditions

Fallopian Tube CancerOvarian CancerPrimary Peritoneal Cavity Cancer

Eligibility

Age Range

18 Years – 120 Years

Sex

FEMALE

DISEASE CHARACTERISTICS:

* Pathologically confirmed ovarian epithelial carcinoma, primary peritoneal cavity carcinoma, or fallopian tube carcinoma

  * Recurrent or persistent disease after treatment with platinum-based chemotherapy

    * Must have platinum-resistant or intolerant disease
* Evaluable disease, as demonstrated by serological (i.e., CA 125), radiological, or pathological studies
* Tumor must express the Wilms Tumor Gene 1 (WT1) peptide, as detected by IHC analysis of banked (i.e., paraffin-embedded) or freshly biopsied tumor nodules

  * Only WT1 tumors graded as moderate to strong (scores 4-12) according to adapted German Immunoreactive Score criteria are considered positive
* No prior or concurrent brain metastases

PATIENT CHARACTERISTICS:

* Karnofsky performance status (PS) 70-100% OR WHO PS 0-1
* Life expectancy ≥ 6 months
* ANC ≥ 1,500/mm³
* Platelet count ≥ 100,000/mm³
* Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60mL/min
* ALT and AST ≤ 2.5 times upper limit of normal (ULN)
* Total bilirubin ≤ 1.5 times ULN
* Adequate pulmonary and cardiac function
* No clinical evidence of cardiopulmonary disease, which, in the opinion of the investigator, would preclude enrollment
* Able to keep scheduled visits
* No known hepatitis B or C infection
* No known HIV positivity
* No evidence of bowel obstruction
* No clinically significant heart disease (New York Heart Association class III or IV)
* No active infections requiring antibiotics within two weeks of study entry
* No serious intercurrent illness requiring hospitalization
* No history of primary or secondary immunodeficiency or autoimmune disease
* No other cancers except nonmelanomatous skin cancer within the past 5 years
* Not pregnant or lactating
* No other issue which, in the opinion of the treating physician, would make the patient ineligible for the study

PRIOR CONCURRENT THERAPY:

* More than 3 weeks since prior anticancer therapy (i.e., chemotherapy, biologic therapy, or immunotherapy)
* No history of whole abdominal radiation therapy

Outcome Measures

Primary Outcomes

Number of Participants Assessed for Safety and Tolerability as Assessed by NCI CTCAE v3.0

Participant toxicity will be evaluated by using NCI CTCAE v3.0

Time frame: 2 years

Total Number of Dose Limiting Toxicities/DLT's

Time frame: 2 years

Mean Overall Survival

Time frame: Up to 3 years

Best Response

Time frame: 1 year

Locations

Memorial Sloan-Kettering Cancer Center, New York, United States

Linked Papers

Phase I dose escalation safety and feasibility study of autologous WT1-sensitized T cells for the treatment of patients with recurrent ovarian cancer

Background This phase I dose escalation trial evaluated the feasibility of production, safety, maximum tolerated dose, and preliminary efficacy of autologous T cells sensitized with peptides encoding Wilms’ tumor protein 1 (WT1) administered alone or following lymphodepleting chemotherapy, in the treatment of patients with recurrent WT1+ ovarian, primary peritoneal, or fallopian tube carcinomas. Methods A 3+3 dose escalation design was used to determine dose-limiting toxicity (DLT). In cohort I, patients received WT1-sensitized T cells dosed at 5×106/m2 (level I) without cyclophosphamide lymphodepletion. In cohorts II–IV, patients received lymphodepleting chemotherapy (a single intravenous dose of cyclophosphamide 750 mg/m2), 2 days prior to the first intravenous infusion of WT1-sensitized T cells administered at escalating doses (2×107/m2 (level II), 5×107/m2 (level III), and 1×108/m2 (level IV)). Results Twelve patients aged 23–72 years, with a median of 7 prior therapies (range 4–14), were treated on the study. No DLT was observed, even at the highest dose level of 1×108/m2 WT1-sensitized T cells tested. Common adverse events reported were grade 1–2 fatigue, fever, nausea, and headache. Median progression-free survival (PFS) was 1.8 months (95% CI, 0.8 to 2.6); 1 year PFS rate 8.3% (95% CI, 0.5 to 31.1). Median overall survival (OS) was 11.0 months (95% CI, 1.1 to 22.6); OS at 1 year was 41.7% (95% CI, 15.2% to 66.5%). Best response was stable disease in one patient (n=1) and progressive disease in the others (n=11). We observed a transient increase in the frequencies of WT1-specific cytotoxic T lymphocyte precursors (CTLp) in the peripheral blood of 9 of the 12 patients following WT1-sensitized T-cell infusion. Conclusion We demonstrated the safety of administration of WT1-sensitized T cells and the short-term increase in the WT1 CTLp. However, at the low doses evaluated we did not observe therapeutic activity in recurrent ovarian cancer. In this heavily pretreated population, we encountered challenges in generating sufficient numbers of WT1-reactive cytotoxic T cells. Future studies employing WT1-specific T cells generated from lymphocytes are warranted but should be done earlier in the disease course and prior to intensive myelosuppressive therapy. Trial registration number NCT00562640. One-sentence summary The authors describe the first human application of autologous WT1-sensitized T cells in the treatment of patients with recurrent ovarian, primary peritoneal, and fallopian tube carcinomas.

Linked Investigators

Roisin E. O'Cearbhaill