Adoptive T Cell Therapy, DC Vaccines, and Hematopoietic Stem Cells Combined With Immune checkPOINT Blockade in Patients With Medulloblastoma

Официальное название

MATCHPOINT - Medulloblastoma Adoptive T Cell Therapy, DC Vaccines, and Hematopoietic Stem Cells Combined With Immune checkPOINT Blockade

Обзор

This is a pilot study in a small number of children and young adults with suspected recurrent/progressive medulloblastoma (MB) looking at the feasibility and safety of adoptive cell therapy plus PD-1 blockade.

Подробное описание

This is a multi-site, single arm, unblinded, uncontrolled pilot study to evaluate the feasibility and safety of ACT + PD-1 blockade in children and young adults with suspected recurrence/progression of Group 3 or 4 (non-SHH/non-WNT) medulloblastoma since completion of definitive focal +/- craniospinal irradiation who are a candidate for surgical resection or biopsy.

After a screening consent is obtained, subjects will undergo standard of care resection for tumor debulking or biopsy for confirmatory diagnosis of disease progression. Tumor tissue will be collected during surgery for tumor debulking or biopsy for total tumor RNA and generation of investigational DC vaccine in parallel. Following biopsy and confirmatory pathologic diagnosis of recurrent MB, patients will be enrolled in the treatment phase of the trial.

After surgery, patients will undergo a mobilized pheresis to collect PBMCs for DC generation and CD34+ HSCs. Amplified tumor RNA obtained from surgically resected or biopsied specimens will be used to generate total tumor RNA-pulsed DCs (TTRNA-DCs) manufactured while patients initiate post-surgical salvage chemotherapy regimen.

Salvage therapy prescribed by treating neuro-oncologist will initiate 1-2 weeks after G-CSF mobilized leukapheresis for 1-3 cycles after which, treatment cycles will be paused, and the patients will receive 3 priming TTRNA-DCs vaccines bi-weekly and undergo a non-mobilized leukapheresis to collect vaccine-boosted lymphocytes for ex vivo T cell expansion and generation of additional TTRNA-DC vaccines. Treatment with salvage therapy will resume with monthly TTRNA-DC vaccines for an additional 1-3 cycles until ex vivo expanded T cells are manufactured and released from the UF cGMP facility.

For ACT, patients will undergo non-myeloablative conditioning with cyclophosphamide/fludarabine followed by infusion of ex vivo expanded tumor-reactive lymphocytes at 3 x 108 cells/Kg, infusion of autologous CD34+ HSCs (targeted dose of 2 x 106 CD34+ HSCs/Kg), PD-1 blockade and three biweekly intradermal TTRNA-DC vaccines to boost T cell engraftment and expansion.

The total immunotherapy regimen will consist of up to 9 intradermal DC vaccines (three -bi-weekly (q2 weeks) for priming, monthly for additional 2-3 cycles during T cell expansion, and three bi-weekly during T cell engraftment), a single intravenous infusion of ex vivo expanded tumor-reactive T cells, and a. single intravenous infusion of autologous HSCs; and PD-1 blockade IV starting with ACT continuing for up to 2 years as long as tolerable and without disease progression.

All patients will receive a full Td booster (5 Lf) IM vaccine prior to Vaccine #1, regardless of booster history. All patients will undergo vaccine site pretreatment with a one-fifth dose of Td (1 Lf) intradermally, at the site of planned DC vaccine, 4-24 hours prior to vaccines #3, #5, #7 and #9.

Вмешательства

• Биопрепарат TTRNA-DC vaccines with GM-CSF
  After chemoradiation subjects will receive the first cycle of dose-intensified TMZ followed by three biweekly TTRNA-DC vaccines with GM-CSF. Monthly DC vaccines will be given during TMZ Cycles 2-5 for Groups A and B and 48-96 hours after completion of TMZ Cycle 6 Day 21 for Group A and 12-36 hours after HSCs for Group B. All subjects will receive an additional two bi-weekly vaccines during Cycle 6 for a total of 10 DC vaccines. All DC vaccines will be embedded with GM-CSF (150 µg per injection)
• Биопрепарат TTRNA-xALT
  All participants will receive a single infusion of T-cells.
• Препарат Td vaccine
  A full Td booster vaccine will be administered IM at Vaccine #1 to all subjects, and vaccine site pretreatment will be administered to all subjects prior to Vaccine#3, #5, #7 and #9.
• Биопрепарат autologous HSCs
  All participants will receive a single intravenous infusion of autologous HSCs.
• Препарат Pembrolizumab
  Participants will receive PD-1 blockade IV starting with ACT continuing for up to 2 years as long as tolerable and without disease progression.

Первичные конечные точки

• Number of participants with immunotherapy-related dose-limiting toxicities after treatment with TTRNA-DCs, TTRNA-xALT and HSCs plus PD1 blockade [Срок оценки: enrollment to completion of DLT window; up to 12 months]
• Number of enrolled participants who receive qualified immunotherapy products out of the total number of participants enrolled. [Срок оценки: enrollment up to 12 months]

Критерии участия

Критерии включения

• Children and young adults ages 4-30 years with suspected recurrence/progression of Group 3 or 4 (non-SHH/non-WNT) MB since completion of definitive focal +/- craniospinal irradiation who are a candidate for surgical resection or biopsy. Of the 6 evaluable subjects, a minimum of 3 slots must be reserved for patients with confirmed Group 4 MB. Patients who are unable to receive radiation therapy due to genetic disorders that put them at significant risk for radiation-induced secondary malignancies (i.e. Gorlin's syndrome or NF1 mutation) are eligible for enrollment at first disease recurrence/progression.
• Patients must currently be prescribed and approved to receive pembrolizumab therapy (patients who have progressed on anti-PD-1 targeting therapy but are otherwise eligible may be enrolled to receive combination with immunotherapy. Patients who have been previously treated with anti-PD-1 targeting therapy alone or in combination with other agents and discontinued for reasons other than toxicity may be enrolled).
• Must be a candidate for surgery/biopsy Or tumor tissue obtained clinically, has been previously stored in a qualified site in a manner suitable for tumor RNA extraction and amplification and sample is made available to the PI.
• Karnofsky or Lansky Performance Status (KPS) ≥ 60% (KPS for > 16 years of age) or Lansky performance Score (LPS) of ≥ 60 (LPS for < 16 years of age)
• Adequate bone marrow and organ function as defined below:

• ANC ≥ 1,000/mcL (unsupported)
• Platelets ≥ 100,000/mcL (unsupported for at least 3 days)
• Hemoglobin ≥ 9 g/dL (may be supported)
• Serum creatinine ≤ 1.5 x IULN OR Creatinine clearance by Cockcroft-Gault ≥ 60 mL/min for patients with serum creatinine > 1.5 x IULN
• Serum total bilirubin ≤ 1.5 x IULN for age OR Direct bilirubin ≤ IULN for patients with total bilirubin > 1.5 x IULN for age
• AST (SGOT) and ALT (SGPT) ≤ 3 x IULN for age
• Cardiac shortening fraction ≥27% or LVEF ≥50% by echocardiogram
• Adequate pulmonary function defined as baseline pulse oximetry of ≥92% on room air
• For females of childbearing potential, negative serum pregnancy test at enrollment
• For women of childbearing potential (WOCBP) must be willing to use acceptable contraceptive methods to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug.

or For males with female partners of childbearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 24 weeks following the last dose of study drug.

• Signed informed consent by patient and/or legally authorized representative

Критерии исключения

this study:

• Prior discontinuation of PD-1 inhibitor treatment due to toxicity.
• Corticosteroids equivalent to ≥ 4mg dexamethasone daily.
• Known HIV, Hepatitis B, or Hepatitis C seropositive.
• Known active infection or immunosuppressive disease.
• Known autoimmune disease requiring medical management with immunosuppressant.
• Pregnancy or lactation, due to possible adverse effects on the developing fetus or infant.
• Treatment with another investigational drug or other intervention within 30 days prior to projected first dose of study treatment (Priming phase with TTRNA-DC).
• Known severe, active co-morbidity, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalization.
• Transmural myocardial infarction within the last 6 months.
• Acute bacterial or fungal infection requiring intravenous antibiotics at time of enrollment.
• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy.
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects.
• Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive.
• Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 2 центра

• Children's National Hospital — Washington D.C.
• University of Florida Health — Gainesville

Идентификаторы

NCT: NCT06514898 · IRB202400861-A · OCR45772

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗