Repeat Intravenous Infusions of B4T2-001 CAR-T Without Lymphodepleting Chemotherapy for Solid Tumors

A Single Arm, Open Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of B4T2-001 CAR-T in Patients With Advanced Solid Tumors

This is an open-label, dose escalation and expansion study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of autologous B4T2-001 CAR-T in subjects with advanced solid tumors including but not limited to advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, advanced pancreatic cancer, advanced non-small cell lung cancer (NSCLC), colorectal cancers (CRC) and metastatic breast cancer that tests positive for BT-001 target antigen according to Immunohistochemistry (IHC). The trial builds off first-in-human results from pilot study per clinicaltrials.gov ID: NCT05621486 to administer multiple infusions of B4T2-001 CAR-T without the need to give preparative chemotherapy (lymphodepletion).

Study Overview

• Status: Recruiting
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Biological: B4T2-001 autologous CAR-T

Detailed Description

This is an open-label dose escalation and expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of lentiviral transduced autologous B4T2-001 CAR-T at up to four Dose Levels. Each treatment Block is composed of three Cycles of B4T2-001 CAR-T administered every 21 days by intravenous route without preparative chemotherapy (lymphodepletion). Subjects with advanced solid tumors will be enrolled. One or more Cycle(s) will be delayed as part of routine dosing plan until (i) absolute neutrophil count (ANC) greater than lower limit of normal (LLN) and (ii) resolution of grade >2 toxicity probably or definitely attributed to prior CAR-T and (iii) CAR-T available. Cycles will discontinue if (i) confirmatory imaging shows progressive disease (PD) and/or (ii) CAR-T cells are unavailable. Each additional Block(s) to begin at least 21 days after third Cycle of prior Block. The next patient(s) may be enrolled at least 21 days after completion of first Cycle of prior patient. The decision for dose escalation decision depends on the safety of first Cycle. Two subjects will be enrolled into each Dose Level. If none experiences a dose-limiting toxicity (DLT), the next cohort of two subjects will be enrolled into the next higher dose level. If a DLT is observed in one subject, four additional subjects will be added into the same dose level. If no additional DLT occur, DL will be escalated to the next higher dose level. If DLT occurs in two or more subjects among two to six subjects at a given dose level, dose escalation will be stopped, and the prior dose level will be expanded to six subjects to confirm maximum tolerated dose (MTD). If there is no more than one subject who experiences a DLT among those six subjects, that dose level is considered the MTD. Response to the treatment will be assessed before and after each Block. CT or MRI or PET for response assessment is anticipated every 60 days till day 180, then every 90 days till the end of the study. If complete response (CR), PD, or partial response (PR) on Day 60's assessment, another imaging study will be performed to confirm findings about 4 weeks later. The tumor marker(s) should be performed at the beginning and end of each Cycle All subjects will receive B4T2-001 CAR-T infusion at a healthcare facility, followed by frequently monitoring at a healthcare facility for at least 7 days to monitor for signs and symptoms of cytokine release syndrome (CRS) including immune effector cell-associated neurotoxicity syndrome (ICANS) and/or hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). One dose of tocilizumab will be administrated on Day 7 of each Cycle as prophylaxis for CRS. The study follows sequential steps: patient screening, apheresis, bridging therapy (as needed), CAR-T infusions and follow up for up to two years. If the safety and tolerability are acceptable and recommended phase 2 dose (RP2D) is determined from the dose escalation stage, dose expansion will be considered.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jin Li, MD,PhD; Phone Number: +86-13761222111; Email: lijin@csco.org.cn

Study Locations

• China
  • China/Shanghai
    • Shanghai, China/Shanghai, China, 200126
      • Recruiting
      • Shanghai East Hospital
      • Contact: Jin Li, MD, PhD; Phone Number: +86-13761222111; Email: lijin@csco.org.cn
    • Shanghai, China/Shanghai, China, 200131
      • Recruiting
      • Shanghai Artemed Hospital
      • Contact: Jun Zhou, MD, PhD; Phone Number: +86-13901906998; Email: zhouj2@gobroadhealthcare.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. The subjects have been fully informed of the possible risks and benefits of participating in this study and have voluntarily signed the informed consent form (ICF).
2. Age: 18-70 years (including 18 and 70 years).
3. ECOG 0-1.
4. With an expected survival of more than 3 months.
5. Patients with histologically or cytologically confirmed locally advanced or metastatic "BT-001 positive" solid tumors. IHC should be within 6 months of apheresis, but maybe extended.
6. Preference for patients who have failed first- or second-line therapy.
7. Having measurable lesions according to RECIST 1.1 (or the latest version).
8. Maximum tumor size less than 4 cm according to RECIST 1.1 (or the latest version).

9. Having sufficient bone marrow, liver, kidney, and lung functions (based on the normal value of the clinical trial sites).

   • ANC and PLT ≥ LLN.
   • Without liver metastases, ALT, AST, or ALP ≤ 2.5×upper limit of normal (ULN); with liver metastases, ALT, AST, or ALP ≤ 5×ULN.
   • Serum creatinine (ScR) ≤ 1.5×ULN, or creatinine clearance > 50 mL/min (calculated according to Cockcroft Gault formula).
   • International normalized ratio (INR) ≤ 1.5×ULN, APTT ≤ 1.5×ULN.
   • Adequate oxygen saturation (≥ 95%) can be maintained without oxygen inhalation.
10. Male or female patients of childbearing potential agree to use effective methods of contraception (such as double-barrier contraceptive methods, condoms, oral or injectable contraceptives, and intrauterine devices) during the study period and within 1 year after infusion.

Exclusion Criteria:

1. Patients who have received the following anti-tumor treatments prior to apheresis:

   1. Cytotoxic therapy within 14 days or 28 days (for chemotherapy with high lymphocytic toxicity such as bendamustine, cyclophosphamide, ifosfamide, fludarabine, cladribine, etc.).
   2. Small molecule targeted therapy within 14 days or at least 5 half-lives, whichever is longer.
   3. Therapy with monoclonal antibody within 21 days including cetuximab.
   4. Therapy with immune checkpoint inhibitors and/or Avastin within 30 days of apheresis.
   5. Immunomodulatory therapy within 14 days.
   6. Radiotherapy within 14 days of apheresis.
   7. Traditional Chinese medicine with anti-tumor indications within 14 days of apheresis.
   8. Investigational agents or treatment within 28 days of apheresis.
   9. Previously treated with CAR-T/TCR-T cells and/or vaccine within 28 days of apheresis.
2. Previously treated with any BT-001-targeted therapy.
3. Brain metastases with central nervous system symptoms.
4. Pregnant (positive pregnancy test prior to dosing) or breast-feeding.
5. Allergic or suspected allergic reaction to any drug and related excipients specified in protocol, e.g., camelid antibody, pre-infusion medication (acetaminophen and diphenhydramine), serum albumin, tocilizumab (or biosimilars of tocilizumab that have been approved for CRS indication), Erbitux/ cetuximab, dimethyl sulfoxide (DMSO), and dextran 40.
6. Patients with positive hepatitis B surface antigen (HBsAg) or hepatitis B virus (HBV) deoxyribonucleic acid (DNA) > 100IU/mL or lower limit of the research center [Only when the detection limit of the research center is higher than 100IU/mL]), or patients with positive HCV antibody.
7. Patients with a history of immunodeficiency, including those who are HIV-positive, or patients with other acquired or congenital immune deficiency, or a history of organ transplantation.
8. Patients with concomitant or previous history of interstitial lung disease or interstitial pneumonia; presence of multiple metastatic lesions in the lungs or a single metastatic lesion ≥ 3 cm in length; patients with inflammation in the lungs or have received extensive radiotherapy.
9. Patients with uncontrolled active infection based on the investigator's judgment.
10. Patients who underwent major surgery within 2 weeks prior to apheresis and not fully recovered.
11. The toxicity of previous anti-cancer therapy, including immunotherapy has not returned to less than or equal to Grade 1 as specified in CTCAE v5.0 or the latest version (except for hair loss, Grade 2 peripheral neuropathy, and stable hypothyroidism treated with hormone replacement therapy).
12. Patients with a history of acute myocardial infarction, unstable angina pectoris, stroke, or transient ischemic attack within 6 months prior to the enrollment, or with NYHA Class 2 or higher congestive heart failure.
13. Patients with chronic diseases requiring treatment with systemic corticosteroids or other immunosuppressants, received systemic corticosteroids (≥ 70 mg prednisone or equivalent dose of other corticosteroids) or other immunosuppressants within 7 days before apheresis, except for the following cases: local, ocular, intra-articular, intranasal, and inhaled glucocorticoid treatment; short term use of glucocorticoids for preventive treatment (such as prevention of contrast medium allergy).
14. Patients with autoimmune diseases.
15. Patients with Crohn's Disease.
16. Patients with a history of uncontrollable mental illness.
17. Any condition in which the investigator considers that the subject is not suitable to participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: B4T2-001 CAR T; Single Arm and Open Label study consisting of dose escalation study design followed by dose expansion phase at determined MTD.	Biological: B4T2-001 autologous CAR-T; Each subject will receive multiple intravenous infusions of B4T2-001 autologous CAR-T without preparative chemotherapy (lymphodepletion)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of B4T2-001 CAR-T will be assessed by the incidence of serious adverse events (SAEs), incidence and severity of adverse events (AEs).	Multiple infusions of B4T2-001 CAR-T.	2 years after B4T2-001 CAR-T
To determine the MTD and RP2D of B4T2-001 CAR-T	The MTD will be determined based on the occurrence of the DLTs according to dose escalation design. RP2D will be defined based on MTD, safety, PK, and preliminary efficacy data.	2 years after B4T2-001 CAR-T

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK parameters: maximum concentration (Cmax)	Maximum concentration (Cmax) with the immunoanalytical method.	Blood sampling for PK will be performed till 2 years after B4T2-001 CAR-T
PK parameters: time of peak concentration (Tmax)	Time to peak concentration (Tmax) with the immunoanalytical method.	Blood sampling for PK will be performed till 2 years after B4T2-001 CAR-T
PK parameters: the last measurable time point (Tlast)	The last measurable time point (Tlast) with the immunoanalytical method.	Blood sampling for PK will be performed till 2 years after B4T2-001 CAR-T
PK parameters: area under the curve (AUCs)	Area under the curve (AUCs)with the immunoanalytical method.	Blood sampling for PK will be performed till 2 years after B4T2-001 CAR-T
Overall response rate (ORR) after administration	ORR is defined as the proportion of subjects who achieve CR or PR after treatment via B4T2-001 CAR T, and the objective tumor response rate will be calculated for patients with measurable disease per by RECIST 1.1 (or the latest version) supplemented by iRecist.	2 years after B4T2-001 CAR-T
Duration of Response (DOR) after administration	DOR is defined as the time from the first documentation of remission (PR or better) to the first documented disease progression evidence (by RECIST 1.1 (or the latest version) supplemented by iRecist) of the responders (who achieve PR or better response).	2 years after B4T2-001 CAR-T
Progress Free Survival (PFS) after administration	PFS is defined as the time from the date of first infusion of the B4T2-001 to the first documented disease progression (according to by RECIST 1.1 (or the latest version) supplemented by iRecist) or death (due to any cause), whichever occurs first.	2 years after B4T2-001 CAR-T
Overall Survival (OS) after administration	OS is defined as the time from the date of first infusion of B4T2-001 CAR-T to death of the subject.	2 years after B4T2-001 CAR-T

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood cytokine levels include interleukin 6 (IL-6), IL-2, IL-4, IL-8, IL-10, TNF-α, and INF-γ with ELISA or equivalent method	Concentration and kinetics of multiple blood cytokines including (IL-6), IL-2, IL-4, IL-8, IL-10, TNF-α, and INF-γ which have the same unit of measure, and using ELISA or equivalent before and after CAR-T and will be evaluated according to actual blood sampling time points.	Blood sampling for cytokine measurement will be performed at planned time points till 2 years after B4T2-001 CAR-T.
H score (0-300)	Explore and evaluate histology before and possibly after CAR-T for expression of BT-001 antigen on the tumor by immunohistochemistry (IHC) to determine the score intensity. "BT-001 positive" refers to a staining of H score of > 150 and preference will be patients with H score of > 200. H score (0-300) will be calculated. High scores are desired.	Planned time points till 2 years after B4T2-001 CAR-T
Overall IHC Score (0-4)	Explore and evaluate histology before and possibly after CAR-T for expression of BT-001 antigen on the tumor by IHC to evaluate the score intensity. "BT-001 positive" refers to an IHC score ≥ 3 and preference will be patients with an IHC score of 4. Overall IHC Score (0-4) will be calculated. High scores are desired.	Planned time points till 2 years after B4T2-001 CAR-T
The percentage of BT-001 positive stained tumor	Explore and evaluate histology before and possibly after CAR-T for heterogeneity of expression of BT-001 antigen on the tumor.	Planned time points till 2 years after B4T2-001 CAR-T
Exploratory tumor biomarker evaluation	Explore and evaluate tumor markers, such as CEA before and possibly after CAR-T.	Planned time points till 2 years after B4T2-001 CAR-T

Collaborators and Investigators

• Sponsor: Shanghai East Hospital
• Collaborators: Bio4T2 LLC
• Investigators: Principal Investigator: Jin Li, MD, PhD, Shanghai East Hospital

Publications and helpful links

General Publications

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• Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4.
• Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litiere S, Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, Caramella C, de Vries EGE; RECIST working group. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017 Mar;18(3):e143-e152. doi: 10.1016/S1470-2045(17)30074-8. Epub 2017 Mar 2. Erratum In: Lancet Oncol. 2019 May;20(5):e242.
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• Kershaw MH, Westwood JA, Darcy PK. Gene-engineered T cells for cancer therapy. Nat Rev Cancer. 2013 Aug;13(8):525-41. doi: 10.1038/nrc3565.
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• Thompson JA, Schneider BJ, Brahmer J, Achufusi A, Armand P, Berkenstock MK, Bhatia S, Budde LE, Chokshi S, Davies M, Elshoury A, Gesthalter Y, Hegde A, Jain M, Kaffenberger BH, Lechner MG, Li T, Marr A, McGettigan S, McPherson J, Medina T, Mohindra NA, Olszanski AJ, Oluwole O, Patel SP, Patil P, Reddy S, Ryder M, Santomasso B, Shofer S, Sosman JA, Wang Y, Zaha VG, Lyons M, Dwyer M, Hang L. Management of Immunotherapy-Related Toxicities, Version 1.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022 Apr;20(4):387-405. doi: 10.6004/jnccn.2022.0020.
• Jo Y, Ali LA, Shim JA, Lee BH, Hong C. Innovative CAR-T Cell Therapy for Solid Tumor; Current Duel between CAR-T Spear and Tumor Shield. Cancers (Basel). 2020 Jul 28;12(8):2087. doi: 10.3390/cancers12082087.
• Del Bufalo F, De Angelis B, Caruana I, Del Baldo G, De Ioris MA, Serra A, Mastronuzzi A, Cefalo MG, Pagliara D, Amicucci M, Li Pira G, Leone G, Bertaina V, Sinibaldi M, Di Cecca S, Guercio M, Abbaszadeh Z, Iaffaldano L, Gunetti M, Iacovelli S, Bugianesi R, Macchia S, Algeri M, Merli P, Galaverna F, Abbas R, Garganese MC, Villani MF, Colafati GS, Bonetti F, Rabusin M, Perruccio K, Folsi V, Quintarelli C, Locatelli F; Precision Medicine Team-IRCCS Ospedale Pediatrico Bambino Gesu. GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma. N Engl J Med. 2023 Apr 6;388(14):1284-1295. doi: 10.1056/NEJMoa2210859.
• Qi C, Gong J, Li J, Liu D, Qin Y, Ge S, Zhang M, Peng Z, Zhou J, Cao Y, Zhang X, Lu Z, Lu M, Yuan J, Wang Z, Wang Y, Peng X, Gao H, Liu Z, Wang H, Yuan D, Xiao J, Ma H, Wang W, Li Z, Shen L. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med. 2022 Jun;28(6):1189-1198. doi: 10.1038/s41591-022-01800-8. Epub 2022 May 9.
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• Hines MR, Knight TE, McNerney KO, Leick MB, Jain T, Ahmed S, Frigault MJ, Hill JA, Jain MD, Johnson WT, Lin Y, Mahadeo KM, Maron GM, Marsh RA, Neelapu SS, Nikiforow S, Ombrello AK, Shah NN, Talleur AC, Turicek D, Vatsayan A, Wong SW, Maus MV, Komanduri KV, Berliner N, Henter JI, Perales MA, Frey NV, Teachey DT, Frank MJ, Shah NN. Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome. Transplant Cell Ther. 2023 Jul;29(7):438.e1-438.e16. doi: 10.1016/j.jtct.2023.03.006. Epub 2023 Mar 9.
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Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2023
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: September 25, 2023
• First Submitted That Met QC Criteria: October 3, 2023
• First Posted (Estimated): October 9, 2023

Study Record Updates

• Last Update Posted (Estimated): October 9, 2023
• Last Update Submitted That Met QC Criteria: October 3, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: B4T2-PRC IIT-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No