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Each subject will receive GC012F injection (CD19-BCMA CAR-T cells) once by intravenous infusion on Day 0.

Other Name: CD19-BCMA CAR-T cells

GC012F injection

He Huang, PhD

Yongxian Hu, PhD

This study is a single-arm, open-label early exploratory clinical trial designed to evaluate the safety, tolerability, and preliminary efficacy of GC012F injection in subjects with refractory GMG. Additionally, the study aims to assess the pharmacokinetic (PK), pharmacodynamic (PD) characteristics, and immunogenicity of GC012F injection in subjects.

This study is a single-arm, open-label early exploratory clinical trial designed to evaluate the safety, tolerability, and preliminary efficacy of GC012F injection in subjects with refractory GMG. Additionally, the study aims to assess the pharmacokinetic (PK), pharmacodynamic (PD) characteristics, and immunogenicity of GC012F injection in subjects.

The trial consists of several phases: screening period, apheresis day, baseline period, lymphodepletion period, pre-infusion assessment period, GC012F infusion period, safety and efficacy follow-up period, long-term follow-up period, and study discontinuation visit (if applicable).

Qualified subjects will undergo apheresis and receive the infusion after the production of CAR-T products. Subjects will undergo lymphodepletion before CAR-T cell infusion and assessment before infusion. Subjects meeting the cell infusion criteria will receive CAR-T cell infusion according to the dose specified in the protocol. Dose adjustments may occur based on safety and clinical efficacy for subjects in the same group or subsequent trial groups.

An Exploratory Clinical Study of GC012F Injection for the Treatment of Refractory Generalized Myasthenia Gravis

The electrocardiography shall be measured after 5 minutes of rest, and assessments included as follows: Heart rate, RR interval, PR interval, QT interval, QRS wave, QT interval and other indexes.

Any untoward medical event that occurs after a subject has administered an investigational product, which may be manifested as a symptom, sign, disease or laboratory abnormality but does not necessarily have a causal relationship with the investigational product.

The full physical examination at least includes assessments of skin, mucosa, lymph nodes, head, neck, chest, abdomen, spine/limbs, and nervous system. A full physical examination needs to be completed only during the screening period, and the physical examination can be performed in subsequent visit as per changes in signs and symptoms.

Laboratory tests include blood test，Coagulation function ，Infectious disease detection and tests recommended by the Investigator

Vital signs shall be measured after 5 minutes of rest, and assessments included as follows: Temperature, oxygen saturation, heart rate, respiratory rate, resting systolic and diastolic blood pressure.

Gracell Biotechnology Shanghai Co., Ltd.

Zhejiang University

Director

Heart and Blood Diseases

Blood and Lymph Conditions

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

BCMA+ cytogenetic high-risk multiple myeloma patients be treated with a single dose of GC012F cells. Total dose of (1-5)\*10\^5/kg cells will be administered at Day 0

GC012F injection is a autologous dual CAR-T targeted BCMA and CD19. A single infusion of CAR-T cells will be administered intravenously.

Weijun Fu

This is a single arm, open label, multi-center prospective study to explory the safety and efficacy of GC012F CAR-T cells in patient diagnosed with high-risk chromosomal abnormalities BCMA+ multiple myeloma(MM).

The main aim of this study is to determin the safety and efficacy of GC012F in cytogenetic high-risk MM. GC012F is an autologus dual chimeric antigen receptor T-cell(CAR-T) therapy that targets B-cell maturation antigen(BCMA) and CD19. This study comprises of a screening phase(less than or equal to 28 days prior to apheresis) followed by apheresis(will occur upon enroiiment); Treatment Phase including autologus stem cell transplant on Day-1 followed by infusion of GC012F on Day0 and then post-infusion assessments from Day1 to Day 84; and a Post-treatment Phase(Day 85 and up to end of the study). Efficacy will be explored to assessed and safety will be closely monitored during the study.

BCMA and CD19 Targeted Fast Dual CART for Chromosomal Abnomalities High-risk BCMA+ Multiple Myeloma

Exploratory Study to Evaluate Efficacy and Safety of GC012F Injection in Chromosomal Abnomalities High-risk BCMA+ Multiple Myeloma

percent of subjects who achieving PR or better after GC012F infusion

Shanghai Changzheng Hospital

Director of Hematology Department

Antineoplastic Agents

All Drugs and Chemicals

Lenalidomide

GC012F will be infused at a dose of1- 3 x 10\^5 CAR+ T cells/kg after receiving lymphodepleting chemotherapy. Lenalidomide maintenance therapy will be given post month 6 at physicians' choice.

GC012F injection is an autologous dual CAR-T targeted BCMA and CD19. A single infusion of CAR-T cells will be administered intravenously.

Juan Du, MD

This is a single-arm, single-center, open-label clinical study to evaluate the safety and efficacy of GC012F in high-risk, transplant eligible patients with NDMM.

Twenty evaluable subjects are planned to be enrolled in this study. Apheresis will be carried out in subjects who meet eligible criteria, and total 2 cycles of induction therapy (three-drug combination regimen based on bortezomib with details determined by the investigator according to the patient's condition) will be selectively given to subjects before or after apheresis. Next, subjects will receive a single infusion of GC012F, and the efficacy assessments will be performed at 1 month, 3 months, and every 3 months within 2 years until the end of the trial (MRD testing is required for each efficacy assessment),

1.Efficacy assessments performed at the 1st and 3rd months after infusion:

1. \<PR: Protocol change or transplantation or follow-up decided by the investigator.
2. ≥PR: MRD positive: Protocol change or transplantation or follow-up decided by the investigator.

MRD negative: Wait for next follow-up.

2.Efficacy assessments performed at the 6th month after infusion and every 3 months thereafter:

1. MRD positive: Protocol change or transplantation or follow-up decided by the investigator.
2. MRD negative: Whether to carry out maintenance treatment using lenalidomide until the end of the trial will be determined by the investigator.

After signing the informed consent form (ICF), subjects will be followed up for efficacy and safety until 2 years after GC012F infusion, or disease progression, or death, or withdrawal of consent, or any intolerable toxicity, whichever comes first. All AEs in subjects, especially infection related symptoms and signs, will be closely monitored during follow-up, and prophylactic treatment will be administered according to clinical practice when necessary. In case of disease progression within 2 years after GC012F infusion, treatment will be administered according to clinical practice, and the survival follow-up (only for the survival status) will be performed every 12 weeks±14 days (2 weeks) until 2 years after infusion, or death, or withdrawal of consent, whichever comes first. For subjects who have undergone transportation or any other clinical routine treatments after GC012F infusion, survival follow-up will be also performed as described above.

Study of FasT CAR-T GC012F Injection in High Risk TE NDMM Patients

Frontline Therapy of GC012F Injection in Transplant Eligible Newly Diagnosed Multiple Myeloma Patients With High-Risk Profile

An assessment of severity grade will be made according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), with the exception of cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS and ICANS should be evaluated according to the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading

ORR defined as proportion of patients achieving PR or better based on IMWG defined response criteria

MRD negative rate is defined as the proportion of participants who achieve MRD negative status by the respective time point

PFS defined as time from date of GC012F infusion to date of first documented disease progression, or death due to any cause, whichever occurs first. DOR defined as time form Month 1 after GC012F infusion to date of 1st documented PD if patients' response deeper or keeping sCR after CAR-T infusion.

DOR defined as time form Month 1 after GC012F infusion to date of 1st documented PD if patients' response deeper or keeping sCR after CAR-T infusion.

Response is defined as participant has met all criteria for PR or better according to IMWG criteria

HRQoL will be assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQC30) items. Subscale and single item scores are reported on a 0-100 scale with higher scores representing better global health status, better functioning, and worst symptoms.

HRQoL will be assessed by the EORTC QLQ-Multiple Myeloma ((MY20) module items. Subscale and single item scores are reported on a 0-100 scale with higher scores representing better global health status, better functioning, and worst symptoms.

Participant-reported health status measured by the EuroQol Group 5-dimension, 5-level (EQ-5D-5L) questionnaire. A total utility score is reported based on the health status, ranging from 0 to 1, where higher values indicate better health utility. The visual analog scale ranges from 0 to 100 where higher values indicate better overall health status.

Participant reported pain measured by Patient Global Impression of Severity (PGIS) Scale. The PGIS is a single item to assess pain severity. The 5-point verbal rating scale ranged from 1 (none) to 5 (very severe).

Levels of GC012F cell expansion (proliferation), and persistence via monitoring CAR-T positive cell counts and CAR transgene level will be reported.

Serum concentrations of Granulocyte-macrophage Colony Stimulating Factor (GM-CSF), interleukin (IL)-6, IL-10, interferon-gamma (IFN-γ), soluble BCMA (sBCMA) and TNF-α after GC012F infusion

Serum concentrations of C-reaction protein (CRP)

Number of patients exhibiting anti-drug antibodies for GC012F and RCL will be reported

R/R multiple myeloma patients be treated with a single dose of GC012F cells.

GC012F injection is a autologous dual CAR-T targeted BCMA and CD19. A single infusion of CART cells will be administered intravenously.

This is a single-arm, non-randomized, open-label study to confirm the RP2D (recommended phase 2 dose) of GC012F injection in patients with Relapsed/Refractory multiple myeloma (RRMM).

This is a single-arm, non-randomized, open-label study to evaluate the RP2D of GC012F injection in patients with Relapsed/Refractory multiple myeloma (RRMM).

Approximately 6-9 eligible patients will be enrolled in escalating dosing cohorts to evaluate the RP2D of GC012F injection. Pts will be enrolled concurrently and assessed for ORR and DLT in respective dosing cohort. Based on this assessment the RP2D will be confirmed.

Table1 Dose Level Dose Level DL-1 DL1 DL2 Dose 1×105 /kg 2×105 /kg 3×105 /kg Patients who signed the informed consent will be screened for inclusion/exclusion criteria, and 3 eligible subjects will be enrolled in DL1.

1. After the DLT observation period of 21 days, if ≤1 of the first 3 subjects has a DLT event, 3 additional subjects will be enrolled in DL1.

   - ORR will be assessed at prespecified timepoints up to 24-weeks post treatment.

   A. If ORR \> 66%, the study concludes and respective dose level will be determined as RP2D B. If ORR≤66%, 3 subjects will be enrolled in DL2
2. If \> 1 of the 3 enrolled subjects has a DLT event, 3 more subjects will be enrolled in the lower dose level

2. During the DLT observation period, if \> 1 of the first 3 subjects has a DLT event, 3 subjects will be enrolled in DL-1 to evaluate safety.

Patients in each dose group will be closely observed for at least 21 days post GCO12F infusion for DLT. Safety and DLT will be assessed by SMC according to definition of protocol for DLT. There will be no fixed dose interval between each dose level and each patient within the dose cohort. In addition, after one year of infusion, patients will be rolled over to a protocol for long-term safety to assess risk of RCL and lentivirus insert in vivo.

This study will be divided into six parts: screening, apheresis, baseline assessment, lymphodeleption, CAR-T cell infusion, and follow-up. Eligible patients will be apheresed and infused after CAR-T product release, patients will receive a 3-days standard F/C chemotherapy regimen for lymphodeleption. The recommend regimens for chemotherpay are as follows

FC regimen:

1. Fludarabine 30 mg/m2/d, iv gtt for 3 days;
2. Cyclophosphamide 300 mg/m2/d, iv for 3 days. GC012F infusion will be performed at 48-72 hours after chemotherapy pretreatment.

After GC012F infusion, subjects will be followed for safety and efficacy up to 1 year, or disease progression, death or withdrawal whichever comes earlier. In case of progression of disease,subsequent survival follow-up (survival state only) will be performed every 84 days (12 weeks) ± 14 days (2 weeks) till death,loss of follow up, or withdraw of consent. If there is no disease progression after 1 year of infusion, the same follow-up for survival will be carried out as mentioned above. End of this study will be 1 year after the last patient received infusion with GC012F.

All patients who complete the study, as well as those who discontinue from the study after receiving GC012F for reasons other than death, will be asked to participate in a 15 years follow-up study to monitor RCL and lentivirus insert sites in vivo.

Study of Dual Targeted CD19/BCMA FASTCART GC012F in Relapsed/ Refractory Multiple Myeloma

Open- Label Phase I Study to Assess the RP2D of GC012F CAR-T in Subjects With Relapsed/Refractory Multiple Myeloma

Incidence of dose-limiting toxicities within 21 days after GC012F infusion.

Incidence of adverse events within 48 weeks after GC012F infusion

Response assessed according to IMWG criteria (Kumar, Shaji et al. 2016), ORR (sCR, CR,VGPR, and PR) within 24 weeks after infusion Minimal Residual Disease (MRD) assessed by Euroflow ;

Progression-free survival (PFS), overall survival (OS), duration of response (DOR) within 48 weeks after infusion (1/3/6/9/12 months after infusion);

CAR-T cell counts and number of CAR gene copies in the blood, bone marrow and/or tumor tissue within 48 weeks after GC012F infusion.

Clinical Professor

CAR-T will be infused at a dose of 0.6,1.5,3 x 10\^5 CAR-T cells/kg after receiving lymphodepleting chemotherapy. Lenalidomide maintenance therapy will be given post month 6 at physicians' choice.

GC012F injection is an autologous dual CAR-T targeted BCMA and CD19. A single infusion of CAR-T cells will be administered intravenously

This is a single-arm, single-center, open-label clinical study to evaluate the safety and efficacy of CAR-T in patients with NDMM.

9-18 evaluable subjects are planned to be enrolled in this study. Apheresis will be carried out in subjects who meet eligible criteria, and total 2 cycles of induction therapy (three-drug combination regimen based on bortezomib with details determined by the investigator according to the patient's condition) will be selectively given to subjects before or after apheresis. Next, subjects will receive a single infusion of CAR-T, and the efficacy assessments will be performed at 1st month, 3rd months, and every 3 months within 2 years until the end of the trial (MRD testing is required for each efficacy assessment)

1.Efficacy assessments performed at the 1st month after infusion:

1. \<PR: Protocol change or follow-up decided by the investigator.
2. ≥PR: Follow-up.

2.Efficacy assessments performed at the 3rd month after infusion and every 3 months thereafter:

1. \<VGPR: Protocol change or follow-up decided by the investigator.
2. ≥VGPR: Maintenance treatment using lenalidomide until progress disease or clinical trial intolerance or termination of trial.

After signing the informed consent form (ICF), subjects will be followed up for efficacy and safety until 2 years after CAR-T infusion, or disease progression, or death, or withdrawal of consent, or any intolerable toxicity, whichever comes first. All AEs in subjects, especially infection related symptoms and signs, will be closely monitored during follow-up, and prophylactic treatment will be administered according to clinical practice when necessary. In case of disease progression within 2 years after CAR-T infusion, treatment will be administered according to clinical practice, and the survival follow-up (only for the survival status) will be performed every 12 weeks±14 days (2 weeks) until 2 years after infusion, or death, or withdrawal of consent, whichever comes first. For subjects who have undergone transportation or any other clinical routine treatments after CAR-T infusion, survival follow-up will be also performed as described above.

Study of FasT CAR-T GC012F Injection NDMM Patients

CAR-T Injection in Transplant In-Eligible Newly Diagnosed Multiple Myeloma Patients

An assessment of severity grade will be made according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), with the exception of cytokine release syndrome (CRS), and immune effector cellassociated neurotoxicity syndrome (ICANS). CRS and ICANS should be evaluated according to the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading

PFS is defined as the time interval from the initiation of induction therapy until disease progression or death (for any reason).

DOR is defined as the time interval from the first assessment of sCR, CR, VGPR or PR to the first assessment of PD or death from any cause after CAR T infusion.

BCMA+ R/R multiple myeloma patients be treated with a single dose of GC012F cells. Total dose of (1-5)\*10E5/kg cells will be administered at Day 0.

This is a single arm, open-label, multi-center prospective study to determine the safety and efficacy of GC012F CAR-T cells in patients diagnosed with BCMA+ refractory/relapsed multiple myeloma (r/r MM).

The main aim of the study is to determine the safety and efficacy of GC012F in r/r MM. GC012F is an autologous dual chimeric antigen receptor T-cell (CAR-T) therapy that targets B-cell maturation antigen (BCMA) and CD19. This study comprises of a Screening Phase (less than or equal to \[\<=\] 28 days prior to apheresis) followed by Apheresis (will occur upon enrollment); Treatment Phase including a conditioning regimen followed by infusion of GC012F and post-infusion assessments from Day 1 to Day 84; and a Post-treatment Phase (Day 85 and up to end of the study). Efficacy will be explored to assessed and safety will be closely monitored during the study.

BCMA and CD19 Targeted Fast Dual CAR-T for BCMA+ Refractory/Relapsed Multiple Myeloma

Exploratory Study to Evaluate Efficacy and Safety of GC012F Injection in BCMA+ Refractory/Relapsed Multiple Myeloma

Bone marrows will be collected in weeks 4, 8, 12, 18, 24 after GC012F infusion.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
An Exploratory Clinical Study of GC012F Injection for the Treatment of Refractory Generalized Myasthenia Gravis	NCT06419166	Refractory Gene...	GC012F injectio...	18 Years - 75 Years	Zhejiang University
BCMA and CD19 Targeted Fast Dual CART for Chromosomal Abnomalities High-risk BCMA+ Multiple Myeloma	NCT04617704	Multiple Myelom...	GC012F injectio...	18 Years -	Shanghai Changzheng Hospital
Study of FasT CAR-T GC012F Injection in High Risk TE NDMM Patients	NCT04935580	Multiple Myelom...	GC012F injectio...	18 Years - 70 Years	Shanghai Changzheng Hospital
BCMA and CD19 Targeted Fast Dual CART for Chromosomal Abnomalities High-risk BCMA+ Multiple Myeloma	NCT04617704	Multiple Myelom...	GC012F injectio...	18 Years -	Shanghai Changzheng Hospital
Study of Dual Targeted CD19/BCMA FASTCART GC012F in Relapsed/ Refractory Multiple Myeloma	NCT05412329	Multiple Myelom...	GC012F injectio...	18 Years - 70 Years	Shanghai Changzheng Hospital
Study of FasT CAR-T GC012F Injection in High Risk TE NDMM Patients	NCT04935580	Multiple Myelom...	GC012F injectio...	18 Years - 70 Years	Shanghai Changzheng Hospital
BCMA and CD19 Targeted Fast Dual CART for Chromosomal Abnomalities High-risk BCMA+ Multiple Myeloma	NCT04617704	Multiple Myelom...	GC012F injectio...	18 Years -	Shanghai Changzheng Hospital
Study of Dual Targeted CD19/BCMA FASTCART GC012F in Relapsed/ Refractory Multiple Myeloma	NCT05412329	Multiple Myelom...	GC012F injectio...	18 Years - 70 Years	Shanghai Changzheng Hospital
Study of FasT CAR-T GC012F Injection NDMM Patients	NCT05840107	Multiple Myelom...	GC012F injectio...	18 Years -	Shanghai Changzheng Hospital
BCMA and CD19 Targeted Fast Dual CAR-T for BCMA+ Refractory/Relapsed Multiple Myeloma	NCT04236011	Multiple Myelom...	GC012F injectio...	18 Years -	Shanghai Changzheng Hospital
An Exploratory Clinical Study of GC012F Injection for the Treatment of Refractory Generalized Myasthenia Gravis	NCT06419166	Refractory Gene...	GC012F injectio...	18 Years - 75 Years	Zhejiang University
BCMA and CD19 Targeted Fast Dual CART for Chromosomal Abnomalities High-risk BCMA+ Multiple Myeloma	NCT04617704	Multiple Myelom...	GC012F injectio...	18 Years -	Shanghai Changzheng Hospital

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