Research Study Utilizing Expanded Multi-antigen Specific Lymphocytes for the Treatment of Solid Tumors (REST)

• ClinicalTrials.gov Identifier: NCT02789228
• Recruitment Status: Recruiting
• First Posted: June 2, 2016
• Last Update Posted: October 14, 2019
• Sponsor: Children's National Research Institute
• Information provided by (Responsible Party): HMeany, Children's National Research Institute

Tracking Information

• First Submitted Date: May 24, 2016
• First Posted Date: June 2, 2016
• Last Update Posted Date: October 14, 2019
• Study Start Date: November 2016
• Estimated Primary Completion Date: September 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 20, 2018)

Incidence of Product-Emergent Adverse Events [ Time Frame: Within 45 days of the last dose of TAA-CT of first infusion and 28 days after the final TAA CTL dose ]

Primary endpoint of the study is defined grade ≥3 infusion-related adverse event occurring within 45 days of the last TAA-CTL dose, grade ≥4 non-hematologic adverse event occurring within 45 days of the last TAA-CTL dose and that are not due to the patient's underlying malignancy or pre-existing co-morbidities or grade ≥3 acute GVHD occurring within 45 days of the last TAA-CTL dose, or any unexpected toxicity of any grade attributed to the infusion of TAA-CTL occurring within 45 days of the last TAA-CTL dose. Toxicities will be defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03

Original Primary Outcome Measures (submitted: June 1, 2016)

Incidence of Product-Emergent Adverse Events [ Time Frame: Within 45 days of the last dose of TAA-CT ]

Primary endpoint of the study is defined grade ≥3 infusion-related adverse event occurring within 45 days of the last TAA-CTL dose, grade ≥4 non-hematologic adverse event occurring within 45 days of the last TAA-CTL dose and that are not due to the patient's underlying malignancy or pre-existing co-morbidities or grade ≥3 acute GVHD occurring within 45 days of the last TAA-CTL dose, or any unexpected toxicity of any grade attributed to the infusion of TAA-CTL occurring within 45 days of the last TAA-CTL dose. Toxicities will be defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03

Current Secondary Outcome Measures (submitted: November 20, 2018)

Tumor associated antigen lymphocytes (TAA-CTL) responses [ Time Frame: 1 year ]

o determine the number of patients who respond to tumor associated antigen lymphocytes (TAA-CTL)

Original Secondary Outcome Measures (submitted: June 1, 2016)

Tumor associated antigen lymphocytes (TAA-CTL) responses [ Time Frame: 2 years ]

o determine the number of patients who respond to tumor associated antigen lymphocytes (TAA-CTL)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Research Study Utilizing Expanded Multi-antigen Specific Lymphocytes for the Treatment of Solid Tumors
• Official Title: Not Provided

Brief Summary

Patients with high-risk solid tumors, those that are refractory to standard up front therapy or relapse after completion of therapy, have a very poor prognosis despite attempts to induce remission with salvage regimen. Novel therapies are critical for this patient population with high-risk cancer.

The ability of tumors to be recognized and lysed by the immune system offers a unique opportunity to aid in tumor eradication by expanding and activating these anti-tumor cells. Through this ability to harness sophisticated and specific immunotherapy, residual or relapsed disease that is resistant to chemotherapy and/or radiotherapy could be eradicated. Prior studies have suggested both safety of expanded specific T cells and efficacy in the setting of melanoma, lymphoma or viral eradication. While this therapy has previously been limited by the versatility of the tumor to down-regulate antigens and evade a single immune-target, the use of multi-antigen specific T cells may permit better and more durable anti-tumor immunity. Thus, the investigators propose to infuse these specific multi-antigen anti-tumor T lymphocytes into patients with high risk solid tumors. This trial will be conducted to demonstrate safety of these cells and generate efficacy and biology data that may be important for future studies that may enhance tumor immunotherapy.

Detailed Description

This protocol is designed as a phase I dose-escalation study. In each treatment group (A and B), patients will be enrolled to one of the following TAA-CTL dose levels:

Dose Level One: 1 x 107 cells/m2 Dose Level Two: 2 x 107 cells/m2 Dose Level Three: 4 x 107 cells/m2 Two to four patients will be enrolled at each dose level until the maximum tolerated dose (MTD) is determined at which point to ensure safety a total 8 patients will be treated at the MTD. Expansion cohorts of Group B patients with Wilms tumor, neuroblastoma, rhabdomyosarcoma, adenocarcinoma and esophageal cancer will be permitted to enroll up to 6 additional patients in each disease group, to be treated at the MTD. Each patient will receive at least one TAA-CTL infusion and may receive a maximum of 8 doses total. Dose escalation will occur once at least 2 patients have completed the 45 day follow up period following their first TAA-CTL infusion. The first and second doses will be administered 45 days apart then additional doses will be spaced every 28 days. The expected volume of each infusion is 1 to 10 cc.

Patients will receive cells due to the presence of refractory disease and/or high risk for disease relapse and/or residual detectable disease following HSCT or conventional therapy at the time of the infusion. Group A and Group B patients will use the dose escalation strategy described above. Ideally, patients should not receive other systemic antineoplastic agents for at least 45 days after the infusion of TAA- CTL (for purposes of evaluation), although such treatment may be added if deemed critical for patient care by the attending physician.

If patients with measurable or evaluable disease have a response of stable disease or better by RECIST criteria (see section 3.2.1) at the day 28 evaluation after dose 2 or subsequent evaluations they are eligible to receive up to 6 additional doses of CTLs at 28 day intervals. Each subsequent doseis expected to be at the enrollment dose level (i.e. no subsequent dose escalation). Following dose 1, if a patient's T cell supply is insufficient for subsequent doses at the enrollment dose level, further treatments may be administered at a lower dose level at the treating physician's discretion.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Solid Tumors

Intervention

Biological: Tumor associated antigen lymphocytes (TAA-CTL)

Pediatric and adult patients who have high-risk solid tumors with known positivity for one or more Tumor Antigen Associated (TAA) (WT1, PRAME and/or survivin) will be eligible to receive Tumor Antigen Associated Cytotoxic T Lymphocytes (TAA CTL). The goal of this cell infusion will be to initiate an immune response against solid tumors that includes multiple antigens and may prevent tumor evasion (through decreased expression of a single antigen).

Study Arms

Experimental: Tumor associated antigen lymphocytes (TAA-CTL)

Tumor associated antigen lymphocytes (TAA-CTL). Three different dosing schedules will be evaluated.

Dose Level One: 1 x 107 cells/m2 Dose Level Two: 2 x 107 cells/m2 Dose Level Three: 4 x 107 cells/m2

Patients will receive cells due to the presence of refractory disease and/or high risk for disease relapse and/or residual detectable disease following conventional therapy at the time of the infusion. Ideally, patients should not receive other systemic antineoplastic agents for at least 6 weeks after infusion of TAA CTL (for purposes of evaluation), although such treatment may be added if deemed critical for patient care by the attending physician.

Intervention: Biological: Tumor associated antigen lymphocytes (TAA-CTL)

• Publications *: Hont AB, Cruz CR, Ulrey R, O'Brien B, Stanojevic M, Datar A, Albihani S, Saunders D, Hanajiri R, Panchapakesan K, Darko S, Banerjee P, Fortiz MF, Hoq F, Lang H, Wang Y, Hanley PJ, Dome JS, Bollard CM, Meany HJ. Immunotherapy of Relapsed and Refractory Solid Tumors With Ex Vivo Expanded Multi-Tumor Associated Antigen Specific Cytotoxic T Lymphocytes: A Phase I Study. J Clin Oncol. 2019 Sep 10;37(26):2349-2359. doi: 10.1200/JCO.19.00177. Epub 2019 Jul 29.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 1, 2016): 32
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2020
• Estimated Primary Completion Date: September 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Recipient procurement inclusion criteria

• Diagnosis of high-risk solid tumors: Ewing sarcoma, Wilms tumor, neuroblastoma, rhabdomyosarcoma, soft tissue sarcomas, osteosarcoma, adenocarcinoma and esophageal carcinoma
• Refractory disease, residual detectable disease following conventional therapy or relapsed disease
• 6 months to 60 years of age at enrollment
• Karnofsky/Lansky score of ≥ 50%
• ANC greater than 500/µL (may be supported with G-CSF)
• Bilirubin ≤ 2.5 mg/dL
• AST/ALT ≤ 5x the upper limit of normal for age
• Serum creatinine < 1.0 mg/dL or 2 x the upper limit of normal for age (whichever is higher)
• Pulse oximetry of > 90% on room air
• Agree to use contraceptive measures during study protocol participation (when age appropriate)
• LVEF > 50% or LVSF > 27 % if history of TBI
• Patient or parent/guardian capable of providing informed consent

Exclusion Criteria:

Recipient Procurement exclusion criteria

• Patients with uncontrolled infections
• Patients with active HIV
• Current evidence of GVHD > grade 2 or chronic GVHD manifestations: bronchiolitis obliterans syndrome, sclerotic GVHD, or serositis.
• Pregnant or lactating females
• Prior immunotherapy with an investigational agent within the last 28 days prior to procurement

Recipient Inclusion to administer cells:

• Steroids less than 0.5 mg/kg/day prednisone (or equivalent)
• Karnofsky/Lansky score of ≥ 50%
• Bilirubin ≤ 2.5 mg/dL
• AST/ALT ≤ 5x the upper limit of normal for age
• Serum creatinine < 1.0 mg/dL or 2x the upper limit of normal for age (whichever is higher)
• Pulse oximetry of > 90% on room air

Recipient Exclusion to administer cells:

• Patients with uncontrolled infections
• Patients who received ATG, Campath, or other T cell immunosuppressive monoclonal antibodies within 28 days prior to TAA CTL infusion
• GVHD > grade 2 or chronic GVHD manifestations: bronchiolitis obliterans syndrome, sclerotic GVHD, or serositis
• Pregnant or lactating females

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months to 60 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Holly Meany, MD; 202-476-2800; HMeany@childrensnational.org

Contact: Fahmida Hoq, MD; 202-476-3634; fhoq@cnmc.org

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02789228
• Other Study ID Numbers: 7497
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: HMeany, Children's National Research Institute
• Study Sponsor: Children's National Research Institute
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Children's National Research Institute
• Verification Date: October 2019