Overview
The goal of this clinical research study is to learn if obecabtagene autoleucel (obe-cel) can help to control newly diagnosed, high-risk B-cell ALL when given as consolidation therapy. Consolidation therapy is given after the first phase of treatment.
Description
Primary Objectives To assess the Efficacy of Obecabtagene autoleucel \[anti-CD19 autologous derived chimeric antigen receptor T-cell (CAR-T)\] in terms of EFS in patients with newly diagnosed high-risk B-cell ALL (defined by baseline high-risk genomics or persistent MRD) post cytoreductive chemoimmunotherapy: 18-month EFS
Secondary Objectives:
- 24-month overall survival (OS)
- For Ph-negative B-cell ALL: Rate of persistent MRD negativity by flow cytometry and NGS at 18 months
- For Ph-positive B-cell ALL: Rate of persistent MRD negativity by flow cytometry, NGS and BCR::ABL1 qPCR (CMR) at 18 months
- Achievement of BCR::ABL1 complete molecular response (CMR) in patients with Ph-positive ALL having persistent measurable disease at any level before obe-cel infusion
- Achievement of NGS MRD negativity amongst patients in CR and not MRD negative before obe-cel
- Time to initiation of next anti-leukemia therapy except HSCT when done in ongoing continued morphological response (patients who did not start next anti-leukemia therapy except HSCT will be censored at the last follow-up/death).
- Rates of HSCT in morphologic remission after obe-cel infusion
- Safety
Exploratory Objectives:
- CAR-T-cell expansion by digital droplet PCR (ddPCR) assay by a manufacturer designated central laboratory (CellCarta) on Days 7, 14, 21, 28, 3 months and then every 3 months up to 12 months post infusion. This will be a send-out test.
- B-cell aplasia (Days 0, 7, 14, 28, monthly up to 3 months and then every 3 months up to 24 months post infusion)
- Measurable residual disease (MRD) negativity by next-generation sequencing (NGS) (at 1 in 105-6 sensitivity) (PB on D14 and PB/BM: Day 28, and then Q3 months up to 24 months post infusion)
- Cytokine panel to study cytokine profile including IL1, IL6, IFNG, TNFalpha from infusion (Days 0, 1, 2, 4, 7, 10, 14, 28)
- Additional correlatives samples to address tumor samples and immune system factors will be collected at baseline, D28 and Q3 months from infusion. These include samples for bulk RNA sequencing of the tumor and germline and single cell RNA sequencing of CAR T-cells as also for assessing the methylation signatures of the CAR T-cells.
risk B-cell ALL (defined by baseline high-risk genomics or persistent MRD) post cytoreductive chemoimmunotherapy: 18-month EFS
Eligibility
- INCLUSION CRITERIA:
In order to be eligible to participate in this study, an individual must meet all of the following criteria:
- Willingness of participant and/or guardian to sign a written informed consent form, which must be obtained prior to initiation of study procedures.
- Period 1: Adults \>=18 years of age
Period 2: Adults and children 3-17 years of age
- Minimum body weight of 35 kg for participation in Period 1 and 18 kg for participation in Period 2.
- Have an activating germline mutation of PTHIR (H223R, I458K, I458R, T410P, or T410R)
- Female participants of reproductive potential must agree to use one form of highly effective contraception. Highly effective contraception includes:
Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post- ovulation methods) and withdrawal are not acceptable methods of contraception.
Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment.
Male sterilization (at least 6 months prior to screening). For female participants in the study, the vasectomized male partner should be the sole partner for that participant for the study duration.
Use of oral, injected, or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormonal vaginal ring or transdermal hormone contraception
Placement of an intrauterine device (IUD) or intrauterine system (IUS)
Barrier methods of contraception used correctly by the male partner: condom or occlusive cap (diaphragm or cervical/ vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
- For males of reproductive potential: use of condoms or other methods described above to ensure effective contraception with partner.
- Stated willingness to comply with all study procedures and availability for the duration of the study, including the ability and willingness to travel to the NIH Clinical Center.
EXCLUSION CRITERIA:
An individual who meets any of the following criteria will be excluded from participation in this study:
- Pregnancy or lactation
- 25-hydroxyvitamin D \<=20 ng/mL. Patients will be eligible for rescreening after a repletion period lasting up to 6 months.
- Clinically significant renal disease with estimated glomerular filtration rate (eGFR) \<=45 mL/ min/1.73 m2.
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2 times the upper limit of normal. If transaminitis is present, patients will be eligible for rescreening for a period of up to 6 months.
- Hgb \<12 gm/dL for women and girls \>=16 years, \<=13 gm/dL for men and boys \>=16 years, and \<=11.5 gm/dL in children \<=15 years. If reduced hemoglobin levels are related to iron, B12, or folate deficiency, patients will be eligible for rescreening after a repletion period lasting up to 6 months.
- Hypersensitivity or intolerance to any active substance or excipient of PTH-IA
- History of surgical removal of all parathyroid glands.
- Treatment with bisphosphonate use within 6 months of screening
- Treatment with denosumab within 3 months of screening
- Treatment with thiazides within 4 weeks of screening
- Any other significant medical conditions that, in the opinion of the study team, may present a concern for participant safety or difficulty with data interpretation.
