A First-in-Human, Phase 1/2, Dose Escalation Study of BOXR1030 T Cells in Subjects With Advanced GPC3-Positive Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- CAR-GPC3 T Cells
- Conditions
- Hepatocellular Carcinoma
- Sponsor
- Sotio Biotech Inc.
- Enrollment
- 7
- Locations
- 8
- Primary Endpoint
- Dose limiting toxicity
- Status
- Active, not recruiting
- Last Updated
- 4 months ago
Overview
Brief Summary
This is a first-in-human (FIH), Phase 1/2, open-label, multicenter study to assess safety and determine the recommended Phase 2 dose (RP2D) of BOXR1030 administration after lymphodepleting chemotherapy (LD chemotherapy) in subjects with glypican-3 positive (GPC3+) advanced solid tumors.
Detailed Description
This is a FIH, Phase 1/2, open-label, multicenter study to assess safety and determine the maximum tolerated dose (MTD) and/or RP2D of BOXR1030 administration after LD chemotherapy in subjects with GPC3+ advanced solid tumors. After signing informed consent and completing all screening assessments, eligible subjects will be enrolled and undergo leukapheresis to obtain T cells for BOXR1030 manufacturing. Subjects will receive a 3-day LD chemotherapy regimen with fludarabine and cyclophosphamide, administered according to institutional standard practice for these drugs, including inpatient administration as appropriate. Subjects must be hospitalized for BOXR1030 administration and will remain hospitalized for 10 days after the infusion. For 28 days after BOXR1030 administration, all subjects must stay within a distance that requires no more than 2 hours of travel to the study site. During the Post-treatment Evaluation Period (within 6 months after BOXR1030 administration), study visits will occur daily for the first week, twice in the second week, and then once weekly at Weeks 3, 4, 6, 9, 12, 15, 18, and 24. Safety (targeted physical examination, adverse event \[AE\] assessment, and clinical laboratory tests) will be evaluated and samples will be collected for endpoint analyses. For 28 days after BOXR1030 administration, subjects will be required to monitor their temperature and complete neurological evaluation via the immune effector cell-associated encephalopathy assessment tool every day (to be administered by site staff during clinical visits and by a caregiver at home on non-clinic days). At regular intervals, antitumor activity will be assessed per RECIST 1.1 and iRECIST criteria. After 6 months of follow-up from BOXR1030 administration, subjects will enter the Long-term Follow-up Period for a total duration of 15 years after BOXR1030 dosing. Study visits are scheduled at Months 7, 9, 11, 13, 15, 18, 21, and 24, every 6 months thereafter until Year 5, and then annually through Year 15. Long-term follow-up assessments will focus on long-term safety and disease status. Subjects whose disease does not progress before Week 24 will enter the Long-term Follow-up at Month 7. Survival status will be checked at these visits.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Aged 18 to 80 years at time of enrollment
- •Body weight \>/= 50kg
- •Able to provide a recent tumor specimen taken within 6 months prior to signing consent and after the initiation of the subject's most recent systemic anti-cancer therapy, for GPC3 expression assessment by immunohistochemistry (IHC). Previously collected tumor tissue older than 6 months at time of GPC3 IHC testing or collected prior to initiation of current or last systemic therapy may be permitted for GPC3 prescreening. If prescreening sample is found to be GPC3+, a new tumor biopsy will be needed to confirm tumor remains GPC3+ in order to proceed.
- •Histologically confirmed advanced unresectable or metastatic hepatocellular carcinoma (HCC), squamous cell carcinoma (SCC) of the lung, myxoid/round cell liposarcoma (MRCLS), or Merkel cell carcinoma (MCC) with GPC3 overexpression by IHC. Subjects must consent to IHC testing in a separate informed consent. Note: Tumor samples will be sent to a central laboratory for GPC3 expression analysis.
- •Documentation of disease progression or refractory disease or intolerance to prior lines of standard-of-care therapies. Patients with tumors with genetic alterations and mutations (e.g., breast cancer gene, epidermal growth factor receptor mutations, and anaplastic lymphoma kinase translocation) who have approved targeted therapies available for their cancer will need to have been treated with such approved therapies or refused such approved targeted therapy for their cancer prior to enrolling in this study.
- •Life expectancy \>16 weeks
- •Have adequate organ function (renal/hepatic/pulmonary)
- •Left ventricular ejection fraction ≥50% by multiple-gated acquisition scan or echocardiogram
- •Eastern Cooperative Group performance status of 0 to 1
- •For subjects with HCC:
Exclusion Criteria
- •Prior treatment with adoptive cell therapy (e.g., CAR T-cell therapy, natural killer cell therapy, engineered T-cell receptor therapy).
- •History of allogenic hematopoietic stem cell transplant.
- •Known untreated CNS tumors or brain metastasis. Subjects are eligible if CNS metastases are asymptomatic, have been treated with radiotherapy for at least 1 month prior to informed consent, are off corticosteroids and have neurologically returned to baseline (residual signs or symptoms related to the CNS treatment are permitted). Imaging obtained for the purpose of CNS metastases management performed during screening must document radiographic stability of CNS lesions for at least 1 month prior to leukapheresis and be performed after completion of any CNS directed therapy. If brain scans are performed, magnetic resonance scans are preferred; however, computed tomography scans are acceptable if magnetic resonance imaging is medically contraindicated. CNS evaluation for subjects with no suspicion of brain tumors in their history is not required for the study. Subjects with known leptomeningeal metastases are excluded.
- •Subjects who have not recovered to \< 1 or baseline from all AEs due to previous therapies (subjects with ≤ grade 2 peripheral neuropathy that has been stable for at least 4 weeks or \< grade 2 endocrine-related AEs that has been stable for at least 4 weeks on replacement therapy).
- •Planned use of any antineoplastic treatment or investigational agent from the time of the first dose of LD chemotherapy through the end of study participation, except for allowed local radiation of lesions for palliation (to be considered non-target lesions after treatment) and hormone ablation.
- •Uncontrolled or life-threatening symptomatic concomitant disease including clinically significant gastrointestinal bleeding or pulmonary hemorrhage within 4 weeks before screening, known symptomatic human immunodeficiency virus (HIV) positive with an acquired immunodeficiency syndrome-defining opportunistic infection within the past 12 months prior to screening, or a current CD4 count \<350 cells/µL, symptomatic active hepatitis B or C checked at screening, or active tuberculosis therapy.
- •Subjects with HIV are eligible if:
- •They have received antiretroviral therapy (ART) as clinically indicated for at least 12 months prior to starting LD therapy and have an HIV viral load less than 40 copies/mL prior to start of LD therapy.
- •They continue on ART as clinically indicated while enrolled on study.
- •CD4 counts\> 350 cells/µL and CD4 counts and viral load are monitored per standard of care by a local health care provider.
Arms & Interventions
GPC3+ solid tumors
One time intravenous administration of BOXR1030 after completion of cyclophosphamide and fludarabine LD chemotherapy
Intervention: CAR-GPC3 T Cells
Outcomes
Primary Outcomes
Dose limiting toxicity
Time Frame: From the time of BOXR1030 administration (Study Day 1) through 28 days after BOXR1030 administration (Study Day 28/Week 4)
Defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 or American Society for Transplantation and Cellular Therapy (ASTCT) criteria for cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome.
RP2D
Time Frame: From the time of BOXR1030 administration (Study Day 1) through 28 days after BOXR1030 administration (Study Day 28/Week 4)
The RP2D may be the same as the MTD, a previously tested dose, or an intermediate/alternative dose below the MTD that is yet unexplored. Alternatively, the RP2D may be selected on the basis of observed safety and activity in dose escalation before the MTD is reached.
MTD
Time Frame: From the time of BOXR1030 administration (Study Day 1) through 28 days after BOXR1030 administration (Study Day 28/Week 4)
Defined as the dose that maximizes the probability of targeted toxicity among doses that satisfy the escalation with overdose control criterion.
Treatment-emergent AEs (TEAEs)
Time Frame: From the time of BOXR1030 administration (Study Day 1) through Week 24
Type, frequency, and severity of TEAEs; clinically significant abnormal safety laboratory findings; and vital signs. TEAEs and laboratory findings according to NCI CTCAE version 5.0 and ASTCT criteria.
Secondary Outcomes
- Overall response rate(From the time of BOXR1030 administration (Study Day 1) until disease progression/recurrence or start of new anti-cancer therapy, whichever came first, assessed up to approximately 15 years)
- Time to progression(From the time of BOXR1030 administration (Study Day 1) until disease progression, assessed up to approximately 15 years)
- Best overall response(From the time of BOXR1030 administration (Study Day 1) until disease progression or death, whichever came first, assessed up to approximately 15 years)
- Progression-free survival(From the time of BOXR1030 administration (Study Day 1) until disease progression or death, whichever came first, assessed up to approximately 15 years)
- Levels of inflammatory markers(From the time of BOXR1030 administration (Study Day 1) until the end of the study, assessed up to approximately 15 years)
- Duration of response(From the date of response for patients with response (complete or partial) until disease progression or death, whichever came first, assessed up to approximately 15 years)
- Clinical benefit rate(From the time of BOXR1030 administration (Study Day 1) until disease progression or death, whichever came first, assessed up to approximately 15 years)
- BOXR1030 T-cell levels in blood(From the time of BOXR1030 administration (Study Day 1) until the end of the study, assessed up to approximately 15 years)
- Time to response(From the time of BOXR1030 administration (Study Day 1) until response, assessed up to approximately 15 years)
- BOXR1030 T-cell characterization in blood(From the time of BOXR1030 administration (Study Day 1) until the end of the study, assessed up to approximately 15 years)