Clinical Trial of Safety, Tolerability and Antitumor Activity of Genetically Engineered T Cells in Combination With Anti-Cancer Agents in Relapsed and Refractory Synovial Sarcoma Expressing New York Esophageal Antigen-1 (NY-ESO-1) and/or LAGE-1a

NCT03697824 | Withdrawn Phase 2 FDA Drug

• 1 other identifier: 209147
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

Adoptive T-cell therapy is a therapeutic approach that aims to generate an anti-tumor T-cell immune response by infusing a cancer subjects own T-cells obtained by leukapheresis, engineered and expanded in-vitro to express a tumor specific T-cell receptor. NY-ESO-1 and LAGE-1a antigens are tumor-associated proteins that have been found in several tumor types, including synovial sarcoma. This is an open-label study to evaluate the safety and efficacy of GSK3377794 (genetically engineered NY-ESO-1 Specific \[c259\] T Cells), in combination with anticancer agents including pembrolizumab in subjects with NY-ESO-1 and/or LAGE-1a positive relapsed and refractory synovial sarcoma. The study will consist of a target expression screening to determine if subjects are human leukocyte antigen (HLA)-A\*02:01, HLA-A\*02:05 and/or HLA-A\*02:06 positive and if their tumors express NY-ESO-1 and/or LAGE-1a, followed by a leukapheresis screening phase of up to 42 days prior to leukapheresis. Eligible subjects will enter a leukapheresis phase followed by lymphodepletion phase with cyclophosphamide and fludarabine. During the treatment phase, subjects will be administered GSK3377794 on Day 1 followed by pembrolizumab infusion once every 3 weeks from Day 22 (or Week 7) for up to 2 years. There will be a long-term follow-up phase from the end of treatment phase and for up to 15 years from the date of GSK3377794 administration.

Conditions

Neoplasms

Keywords

HLA-A2+; Synovial Sarcoma; pembrolizumab; NY-ESO-1; GSK3377794; LAGE-1a

Outcome Measures

Primary Outcomes (3)

• Number of subjects with treatment limiting toxicities (TLT)

  The following toxicities will be considered as TLTs: Any \>=Grade 4 adverse event (AE) except for Grade 4 fever and chills and Grade 4 hypoalbuminemia or abnormal electrolytes that are responding to supplementation/correction; Grade 3 non-infectious pneumonitis; Any other Grade 3 AE (excluding pneumonitis), that does not improve to Grade 2 within 7 days after onset despite medical management and supportive care; Any AE that permanently prevents subject from dosing with pembrolizumab in this trial.

  Up to 2 years

• Number of subjects with AEs

  An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study intervention, whether or not considered related to the study intervention.

  Up to 2 years

• Severity of AEs

  The severity of AEs will be graded according to National Cancer Institute-Common terminology criteria for adverse events (NCI-CTCAE) version 4.03.

  Up to 2 years

Secondary Outcomes (18)

• Number of subjects with serious adverse events (SAEs)

  Up to 2 years

• Number of subjects with AE /SAEs leading to pembrolizumab administration delay, interruptions, and withdrawals

  Up to 2 years

• Number of subjects with abnormal hematology parameters

  Up to 2 years

• Number of subjects with abnormal clinical chemistry parameters

  Up to 2 years

• Number of subjects with abnormal urine parameters

  Up to 2 years

Study Arms (1)

GSK3377794+pembrolizumab

EXPERIMENTAL

After screening, eligible subjects will enter a leukapheresis phase, followed by lymphodepletion phase where they will be administered fludarabine and cyclophosphamide. On Day 1, subjects will receive a single dose of GSK3377794 administered as an intravenous infusion of 1 to 6 x10\^9 total transduced cells. On Day 22, subjects will be administered pembrolizumab at a dose of 200 milligrams (mg) once every 3 weeks for adults and 2 mg/kilogram (kg) (up to 200 mg) once every 3 weeks for children for up to 35 cycles (2 years) or until subsequent disease progression.

Drug: GSK3377794; Drug: Pembrolizumab; Drug: Fludarabine; Drug: Cyclophosphamide

Interventions

GSK3377794 DRUG

GSK3377794 is genetically engineered NY-ESO-1 Specific (c259) T cells.

GSK3377794+pembrolizumab

Pembrolizumab DRUG

Pembrolizumab will be administered at a dose of 200 mg once every 3 weeks for adults and 2 mg/kg (up to 200 mg) once every 3 weeks for children.

GSK3377794+pembrolizumab

Fludarabine DRUG

Fludarabine will be used as a lymphodepleting chemotherapy.

GSK3377794+pembrolizumab

Cyclophosphamide DRUG

Cyclophosphamide will be used as a lymphodepleting chemotherapy.

GSK3377794+pembrolizumab

Eligibility Criteria

• Age: 10 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Target Expression Screening Phase: Subject must be \>=10 years of age at the time of signing the informed consent. Younger subjects may only be enrolled upon consultation with Sponsor.
• Pathologically or histologically confirmed advanced synovial sarcoma that is either metastatic or unresectable and is either currently being treated with or has completed at least one line of standard chemotherapy regimen or subject is intolerant to it. Subjects can also undergo leukapheresis prior to initiating first line or standard therapy.
• Radiologically detectable disease.
• Life expectancy \>=3 months.
• In the investigator's opinion, the subject is suitable for leukapheresis and, subsequently, for GSK3377794 and pembrolizumab infusion.
• An archival biopsy or fresh biopsy (if collected as part of standard of care) of tumor tissue is required to perform antigen expression analysis.
• Male or female subjects will be included. Contraception requirements will apply at the time of leukapharesis and treatment.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol. For subjects \<18 years of age (or the legal minimum age in the relevant country) their legal guardian must give informed consent. Pediatric subjects will be included in age-appropriate discussion in order to obtain verbal assent.
• Leukapheresis Phase: In addition to the criteria mentioned above, the following criteria must also apply.
• Subject's tumor has been reviewed by the GlaxoSmithKline (GSK)-designated laboratory and confirmed as meeting the pre-defined threshold for expression of NY-ESO-1 and/or, if tested, LAGE-1a, using archival or fresh (if taken as standard of care) biopsy.
• HLA-A\*02:01, HLA-A\*02:05, and/or HLA-A\*02:06 by high resolution testing.
• Left ventricular ejection fraction \>=40%, or Fractional Shortening \>=28%.
• Performance status: ECOG of 0-1 or for subjects \<=10 years of age, Lansky \>60.
• Subject must have adequate organ function 7 days prior to leukapheresis.
• Male or female subjects will be included. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. a) Male subjects are eligible to participate if they agree to the following during the intervention period starting at the first dose of chemotherapy for at least 12 months after receiving the T-cell infusion, or 4 months after there is no evidence of persistence/ gene modified cells in the subject's blood, whichever is longer. Must use effective contraception for at least 4 months after the last dose of pembrolizumab if this time frame is longer than the duration of contraception required in the context of chemotherapy and gene modified cells.

You may not qualify if:

• Target Expression Screening Phase: Prior malignancy other than synovial sarcoma: a) Subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. b) Subjects with previous malignancies that have been definitively treated, and have been in remission may be enrolled upon consultation with sponsor Medical Monitor or designee.
• Previous treatment with genetically engineered NY-ESO-1 specific T cells.
• Previous NY-ESO-1 vaccine.
• Prior gene therapy using an integrating vector.
• Previous allogeneic hematopoietic stem cell transplant.
• Clinically significant systemic illness (e.g. serious active infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgment of the Investigator would compromise the subject's ability to tolerate protocol therapy or significantly increase the risk of complications.
• Leukapheresis Phase: In addition, to the above criteria subjects are not eligible for leukapharesis if any of the following criteria apply:
• Has chronic, recurrent, or active autoimmune/immune-mediated disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• Uncontrolled intercurrent illness including, but not limited to: a) Ongoing or active infection requiring systemic therapy; b) Clinically significant cardiac disease defined by congestive heart failure New York Heart Association (NYHA) Class \>1; c) Uncontrolled clinically significant arrhythmia in last 6 months; d) Acute coronary syndrome (angina or myocardial infarction) in last 6 months; e) Severe aortic stenosis or symptomatic mitral stenosis; f) Inadequate pulmonary function with mechanical parameters \<40% predicted (Forced expiratory volume in 1 second \[FEV1\], Forced vital capacity \[FVC\], Total lung capacity \[TLC\], Diffusing capacity of the lung for carbon monoxide \[DLCO\]); g) Interstitial lung disease (subjects with existing pneumonitis as a result of radiation are not excluded; however, subjects cannot be oxygen dependent); h) Any other illness that in the judgment of the Investigator would compromise the subjects ability to tolerate protocol therapy or significantly increase the risk of complications
• Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per investigator assessment).
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Corrected QT interval duration (QTc) \>450 milliseconds (msec) or QTc \>480 msec for subjects with bundle branch block. The QTc is the QT interval corrected for heart rate according to Bazett's formula (QTcB), Fridericia's formula (QTcF), and/or another method, machine-read or manually over-read.
• Subject has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide, fludarabine, other agents used in the study (Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule).
• Has severe hypersensitivity (\>=Grade 3) to pembrolizumab and/or any of its excipients.
• Pregnant or breastfeeding females (due to risk to fetus or newborn).

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Merck Sharp & Dohme LLC: collaborator

MeSH Terms

Conditions

Neoplasms; Sarcoma, Synovial

Interventions

pembrolizumab; fludarabine; Cyclophosphamide

Condition Hierarchy (Ancestors)

Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Sarcoma

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is an open-label, single arm treatment study.

Study Record Dates

• First Submitted: October 4, 2018
• First Posted: October 5, 2018
• Study Start: February 25, 2019
• Primary Completion: July 18, 2022
• Study Completion: July 18, 2022
• Last Updated: October 29, 2019

Record last verified: 2019-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.