Hypofractionated Radiation and Lymphodepleting Chemotherapy Followed by B7-H3-CAR T Cells for the Treatment of Pediatric Patients with Relapsed or Refractory Sarcomas

Status: active

This phase I trial tests the safety and antitumor activity of hypofractionated radiation therapy and lymphodepleting chemotherapy followed by B7-H3-chimeric antigen receptor (CAR) T cells for the treatment of pediatric patients with sarcoma that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). Hypofractionated radiation therapy delivers higher doses of radiation therapy over a short period of time with the goal of killing more tumor cells with fewer side effects, and may make the immune system more receptive to the CAR T cell therapy. The chemotherapy drugs given in this study, fludarabine and cyclophosphamide, are used to help prepare the body for the new CAR T cells and allow them to grow. T cells are part of the healthy immune system and can kill tumor cells. The T cells given in this study will be collected from the patient and will have a new gene put in them that makes them able to recognize B7-H3, a protein on the surface of tumor cells. These B7-H3-specific CAR T cells may help the body's immune system identify and kill B7-H3+ sarcoma cells. This study will test whether giving hypofractionated radiation therapy and lymphodepleting chemotherapy followed by B7-H3-CAR T cells is safe and tolerable in pediatric patients with relapsed or refractory sarcoma, and whether this approach has activity against B7-H3+ sarcomas.

Inclusion Criteria

COLLECTION AND MANUFACTURING: A previously collected, autologous leukapheresis product may be used for T cell production
COLLECTION AND MANUFACTURING: Age ≤ 21 years old
COLLECTION AND MANUFACTURING: B7-H3+ sarcoma; B7-H3 expression will be evaluated by standard immunohistochemistry (IHC) using any previously obtained biopsy; a tumor is considered B7-H3 positive with a H-score of ≥ 100 * Osteosarcoma * Ewing Sarcoma * Rhabdomyosarcoma * Non-rhabdomyosarcoma soft tissue sarcomas
COLLECTION AND MANUFACTURING: Evidence of relapsed (cancer that has completely responded [i.e., no evidence of disease using standard imaging modalities] to first-line therapy but has recurred for the first or subsequent time); or refractory (cancer that does not respond completely to treatment; cancer may be resistant at the beginning or may become resistant during treatment) disease after standard first-line therapy
COLLECTION AND MANUFACTURING: Evaluable disease with presence of at least one lesion amenable to hypofractionated radiation therapy * For dose expansion cohort: participants must also have additional evaluable disease beyond planned radiation field
COLLECTION AND MANUFACTURING: Estimated life expectancy of > 12 weeks
COLLECTION AND MANUFACTURING: Karnofsky or Lansky (age-dependent) performance score ≥ 60 * Participants with mobility limitations due to prior surgical intervention (i.e., amputation) but who are up in wheelchair or with other assistive devices will be considered ambulatory for the purpose of performance score determination
COLLECTION AND MANUFACTURING: For females of child-bearing age: * Not pregnant with negative serum pregnancy test within 7 days prior to enrollment * Not lactating with intent to breastfeed
COLLECTION AND MANUFACTURING: Participants must be eligible to undergo autologous apheresis or have an available previously collected autologous apheresis product
TREATMENT: Age ≤ 21 years old at the time of manufacturing
TREATMENT: B7-H3+ sarcoma
TREATMENT: Evidence of relapsed or refractory disease after standard first-line therapy
TREATMENT: Evaluable disease with the presence of at least one lesion amenable to hypofractionated radiation therapy * For dose expansion cohort: participants must also have additional evaluable disease beyond the planned radiation field
TREATMENT: Estimated life expectancy of > 8 weeks
TREATMENT: Karnofsky or Lansky (age-dependent) performance score ≥ 60 * Participants with mobility limitations due to prior surgical intervention (i.e., amputation) but who are up in wheelchair or with other assistive device will be considered ambulatory for purpose of performance score determination
TREATMENT: Adequate cardiac function defined by echocardiogram with left ventricular ejection fraction ≥ 50%
TREATMENT: Adequate renal function as defined: * 1 to < 2 years: Maximum serum creatinine 0.6 mg/dL (male), 0.6 mg/dL (female) * 2 to < 6 years: Maximum serum creatinine 0.8 mg/dL (male), 0.8 mg/dL (female) * 6 to < 10 years: Maximum serum creatinine 1 mg/dL (male), 1 mg/dL (female) * 10 to < 13 years: Maximum serum creatinine 1.2 mg/dL (male), 1.2 mg/dL (female) * 13 to < 16 years: Maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female) * ≥ 16 years: Maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)
TREATMENT: Adequate pulmonary function defined as pulse oximetry ≥ 92% on room air
TREATMENT: Total bilirubin ≤ 3 times the upper limit of normal for age, except in subjects with Gilbert’s syndrome
TREATMENT: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age
TREATMENT: Hemoglobin ≥ 7g/dL (can be transfused)
TREATMENT: Platelet count ≥ 50,000/μL (can be transfused)
TREATMENT: Absolute neutrophil count (ANC) ≥ 1000/μL
TREATMENT: Has recovered from all National Cancer Institute (NCI) Common Terminology for Adverse Events (CTAE) grade III-IV, non-hematologic acute toxicities from prior therapy
TREATMENT: For females of child-bearing age: * Not pregnant with negative serum pregnancy test within 7 days prior to enrollment * Not lactating with intent to breastfeed
TREATMENT: If sexually active, agreement to use contraception until 3 months after T cell infusion

Exclusion Criteria

COLLECTION AND MANUFACTURING: Known primary immunodeficiency
COLLECTION AND MANUFACTURING: Known HIV positivity
COLLECTION AND MANUFACTURING: Severe, uncontrolled intercurrent bacterial, viral, or fungal infection
COLLECTION AND MANUFACTURING: Known active malignancy other than the B7-H3+ sarcoma being treated on study
COLLECTION AND MANUFACTURING: Rapidly progressive disease (as assessed by the study principal investigator (PI)s, with consideration for proximity to critical structures)
COLLECTION AND MANUFACTURING: Presence of intracranial or spinal cord disease
COLLECTION AND MANUFACTURING: Known underlying medical condition(s) for which, in the investigator’s opinion, participation in this trial would not be in the best interest of the participant (e.g., compromises the health of the subject) or that could prevent, limit, or confound protocol assessments
COLLECTION AND MANUFACTURING: Known severe hypersensitivity to corn starch or hydroxyethyl starch
TREATMENT: Known primary immunodeficiency
TREATMENT: Known HIV positivity
TREATMENT: Severe, uncontrolled intercurrent bacterial, viral, or fungal infection
TREATMENT: Known active malignancy other than the B7-H3+ sarcoma being treated on study
TREATMENT: Receiving systemic steroid therapy exceeding the equivalent of 0.5 mg/kg/day of methylprednisolone, ≤ 7 days prior to CAR T cell infusion
TREATMENT: Receiving systemic therapy ≤ 14 days prior to start of protocol therapy, which will interfere with the activity of the CAR product (in the opinion of the study PIs)
TREATMENT: Received radiation therapy within the 4 weeks prior to start of protocol therapy
TREATMENT: Rapidly progressive disease (as assessed by the study PIs, with consideration for proximity to critical structures)
TREATMENT: Presence of intracranial or spinal cord disease
TREATMENT: Known underlying medical condition(s) for which, in the investigator’s opinion, participation in this trial would not be in the best interest of the participant (e.g., compromises the health of the subject) or that could prevent, limit, or confound protocol assessments
TREATMENT: Known severe hypersensitivity to corn starch or hydroxyethyl starch

PRIMARY OBJECTIVE:

I. To evaluate the safety of autologous anti-B7-H3 CAR T cells (B7-H3-CAR T cell) therapy after priming with hypofractionated radiation therapy (HFRT) and lymphodepleting chemotherapy in patients ≤ 21 years of age with relapsed/refractory B7-H3+ sarcomas.

SECONDARY OBJECTIVES:

I. To describe the antitumor activity of B7-H3-CAR T cells in combination with HFRT.

II. To determine if B7-H3-CAR T cells traffic to tumor sites after combination treatment with HFRT.

EXPLORATORY OBJECTIVES:

I. To assess the immunophenotype, expansion, persistence, and functional status of B7-H3-CAR T cells.

II. To characterize the systemic immune profile throughout the course of protocol treatment.

III. To describe the local tumor microenvironment in response to HFRT and B7-H3-CAR T cell therapy and identify mechanisms of response and resistance.

IV. To identify germline and somatic genetic variants in deoxyribonucleic acid (DNA) damage repair pathways and evaluate for associations with response to protocol therapy.

V. To measure cell free DNA through the course of protocol treatment and correlate with the presence of B7-H3-CAR T cells and response to therapy.

OUTLINE:

Patients undergo apheresis to obtain T cells for manufacturing. In the treatment portion, patients undergo HFRT to 1-5 lesions over 5 or 8 treatments, with the last treatment on day -2. Patients also receive fludarabine intravenously (IV) on days -5 to -2 and cyclophosphamide IV on days -3 and -2. Patients then receive B7-H3-CAR T cells IV over 30 minutes on day 0 or +1. Patients who received clinical benefit and have additional cell product may receive optional additional treatment course with fludarabine, cyclophosphamide and B7-H3 CAR T cells at least 4 weeks after initial dose, which may or may not include additional radiation. Patients undergo diagnostic imaging and blood sample collection throughout the study. All patients are evaluated for a post-treatment biopsy and may choose to be evaluated for a pre-treatment biopsy. Patients with bone marrow involvement of their tumor may undergo bone marrow aspiration and/or biopsy throughout the study.

After completion of study treatment, patients are followed on study for 1 year, with additional long term follow-up for up to a total of 15 years.

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Hypofractionated Radiation and Lymphodepleting Chemotherapy Followed by B7-H3-CAR T Cells for the Treatment of Pediatric Patients with Relapsed or Refractory Sarcomas

Inclusion Criteria

Exclusion Criteria

United States

Tennessee

Memphis

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Hypofractionated Radiation and Lymphodepleting Chemotherapy Followed by B7-H3-CAR T Cells for the Treatment of Pediatric Patients with Relapsed or Refractory Sarcomas

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