Study of Efficacy and Safety of CRC01 in Adult Large B-cell Lymphoma and B-cell Acute Lymphoblastic Leukemia Patients

An Open-label, Multi-center, Single-arm Phase 1/2 Study to Assess Tolerability, Safety and Efficacy of CRC01 in Adult Patients With Relapsed or Refractory Large B-cell Lymphoma and B-cell Acute Lymphoblastic Leukemia

This is a multi-center, phase I/II study to determine the efficacy and safety of CRC01 in adult patients with relapsed or refractory large B-cell lymphoma and B-cell Acute Lymphoblastic Leukemia.

Cohort A:

Inclusion Criteria:

1. ≥ 19 years of age and provided written informed consent

2. Histologically confirmed following large B-cell lymphomas according to the World Health Organization classification 2017

   • Diffuse large B-cell lymphoma, not otherwise specified Including Large cell transformation from follicular lymphoma (Transformed follicular lymphoma)
   • High-grade B-cell lymphoma, not otherwise specified
   • High-grade B-cell lymphoma with double-hit/triple-hit
   • Primary mediastinal large B cell lymphoma

3. Relapsed or refractory disease after ≥ two lines of chemotherapy including rituximab, anthracycline and either having failed autologous Hematopoietic stem cell transplantation (ASCT) or being ineligible for or not consenting to ASCT.

4. At least one measurable lesion (Long diameter ≥ 1.5cm)

5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

6. Adequate renal and hepatic functions based on the laboratory test results

   • Total Bilirubin ≤ 2.0mg/dL with the exception of patients with Gilbert-Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is ≤ 3 X ULN and direct bilirubin ≤ 1.5 X ULN.
   • Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 3 X Upper Limit of Normal (ULN) for age with exception of liver metastasis; patients with liver metastasis may be included if their AST and ALT are ≤ 5 X ULN.
   • Serum creatinine ≤ 1.5 X ULN
   • Estimated Glomerular Filtration Rate (eGFR) ≥ 60mL/min/1.73m2

7. Adequate hematologic function without transfusions within 2 weeks prior to screening for the study defined as followings:

   • Hemoglobin > 8.0g/㎗
   • Absolute Neutrophil Count (ANC) > 1,000/㎕
   • Absolute Lymphocyte Count (ALC) ≥ 300/㎕
   • Platelets ≥ 50,000/㎕

8. Must have a minimum level of pulmonary reserve defined as;

   • ≤ Grade 1 dyspnea per Common terminology criteria for adverse events (CTCAE) v5.0
   • pulse oxygenation > 91% on room air

9. Hemodynamically stable, without pericardial effusion and Left Ventricle Ejection Fraction (LVEF) ≥ 50% confirmed by Echocardiogram (ECG) or Multigated Radionuclide Angiography (MUGA)

10. Must have an apheresis product of non-mobilized cells accepted for manufacturing

11. Life expectancy ≥ 12 weeks

12. Women of child-bearing potential and all male participants must agree to use highly effective methods of contraception for at least 12 months following CRC01 infusion and until CRC01 are no longer present by PCR on two consecutive tests

Exclusion Criteria:

1. Patients with the following medical history

   • Previous or concurrent malignancy with the following exceptions:

     • Adequately treated basal cell or squamous cell carcinoma without evidence of recurrence for at least 3 years prior to the study
     • In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study
     • A primary malignancy which has been completely resected and in complete remission for ≥ 5 years

   • Unstable angina and/or myocardial infarction within 12 months prior to screening

   • Thromboembolic events, pulmonary embolism or bleeding diatheses within 6 months prior to screening

   • Hypoxemia, significant pleural effusion or significant EKG findings within 6 months prior to the screening

2. Patients with the following concurrent disease at screening:

   • Central Nervous System (CNS) involvement by malignancy by MRI at screening
   • Active infection with hepatitis B (HBsAg positive. But, in case of HBcAb IgG positive, the patient can be enrolled in this study if he/she takes prophylactic anti-viral agent.)
   • Active infection with hepatitis C (HCV RNA positive)
   • Human immunodeficiency virus (HIV) positive
   • Active neurological auto-immune or inflammatory disorder (e.g. Guillain Barre Syndrome, Amyotrophic Lateral Sclerosis)
   • Ventricular tachycardia and atrial fibrillation with rapid ventricular response not controlled with medical treatment within 3 months prior to screening

3. Rapidly progressing the disease as per investigator's discretion

4. Had major surgery requiring general anesthesia or mechanical ventilation within 4 weeks prior to screening (For video-assisted thoracoscopic surgery (VATS) or open-and-closed (ONC) surgery can be applied with within 2 weeks prior to screening.)

5. Severe infection requiring anti-bacterial, anti-fungal or anti-viral medication or uncontrolled active infection

6. The following treatment history is excluded:

   • Prior treatment with any prior anti-CD19/anti-CD3 therapy or any other anti-CD19 therapy
   • Prior treatment with any adoptive T cell therapy
   • Treatment with any prior gene therapy product
   • Prior allogeneic HSCT
   • Patients on oral anticoagulation therapy

7. Eligible for and consenting to ASCT

8. Use of investigational medicinal product/device within 4 weeks prior to screening

9. Pregnant or lactating women

10. Hypersensitivity reaction to the excipients of CRC01 cell product

11. The following treatments are excluded:

    • Anti-neoplastic therapies including chemotherapy, biologic agents, retinoid therapy, radiotherapy, immune therapy, hormonal therapy, etc. other than lymphodepleting chemotherapy within 2 weeks of leukapheresis and within 2 weeks of CRC01 infusion
    • Steroids: therapeutic doses of steroids must be stopped > 7 days prior to leukapheresis and > 5 days prior to CRC01 infusion. However, the following physiological replacement doses of steroids are allowed: < 6 mg/m2/day hydrocortisone or equivalent
    • Immunosuppression: any immunosuppressive medication must be stopped > 4 weeks prior to leukapheresis and > 4 weeks prior to CRC01 infusion
    • Antibody use including anti-CD20 therapy within 4 weeks prior to CRC01 infusion
    • CNS disease prophylaxis must be stopped > 1 week prior to CRC01 infusion (e.g. intrathecal methotrexate)

Cohort B :

Inclusion Criteria :

1. ≥ 19 years of age and provided written informed consent to voluntarily participate in this trial

2. Relapsed or refractory B-cell lymphoblastic leukemia with one of the following:

   • Primary refractory: Newly diagnosed and refractory to 2 or more cycles of standard chemotherapy
   • Relapsed within 12 months of the first complete remission
   • Chemorefractory: Refractory to 1 cycle of chemotherapy conducted after relapse
   • Relapsed after or refractory to two or more lines of chemotherapy
   • Relapsed or refractory 100 days after allogeneic HSCT

3. (within 4 weeks prior to screening) Blast of > 5% identified in the BM

4. (within 4 weeks prior to screening) BM or peripheral blood blast confirmed CD19-positive.

   Specifically, those with prior treatment with any other anti-CD19 therapy must be confirmed to show CD19 ≥ 90%.

5. Philadelphia chromosome positive with one of the following:

   • Unable to take tyrosine kinase inhibitors (TKIs) due to side effects
   • Relapsed or refractory despite treatment with two or more TKIs

6. ECOG performance status of 0-1

7. Confirmed adequate hematologic function defined as follows:

   • Absolute neutrophil count (ANC) ≥ 500/μL. However, exceptions are made in cases where the Investigator determines that cytopenia is related to the leukemia and may be recovered with leukemia treatment.
   • Platelet count ≥ 50,000/μL. However, exceptions are made in cases where the Investigator determines that cytopenia is related to the leukemia and may be recovered with leukemia treatment.
   • Absolute lymphocyte count ≥ 200/μL

8. Adequate renal and hepatic functions confirmed based on the laboratory test results:

   • Total Bilirubin ≤ 2.0 mg/dL (for patients with Gilbert-Meulengracht syndrome, total bilirubin ≤ 3 × ULN and direct bilirubin ≤ 1.5 × ULN)
   • AST and ALT ≤ 3 × ULN
   • Serum creatinine ≤ 1.5 × ULN or eGFR* ≥ 45 mL/min/1.73 m2 *MDRD-GFR (mL/min/1.73 m2) = 186 × (serum creatinine)-1.154 × (age)-0.203 (× 0.742 for females)

9. Confirmed to have a minimum level of pulmonary reserve according to the following criteria:

   • ≤ Grade 1 dyspnea per CTCAE v5.0
   • Pulse oxygenation > 91% on room air

10. Hemodynamically stable, without pericardial effusion, and LVEF ≥ 50% confirmed by ECHO or MUGA scan at Screening

11. Capable of obtaining through leukapheresis non-mobilized cells adequate for CRC01 manufacturing

12. Life expectancy of ≥ 12 weeks

13. Consented to comply with the site visit and test schedules for Primary Follow-up and Secondary Follow-up in accordance with the Protocol for the duration of the Study

14. WOCBP or male subjects who are willing to use appropriate contraceptive methods* for at least 12 months following CRC01 treatment and until CRC01 is no longer detected through two consecutive PCR tests * Hormonal contraceptives, placement of intrauterine system, double barrier method (simultaneous use of contraceptive vaginal diaphragm or cervical cap and male condom, along with spermicide), sterilization (vasectomy, bilateral tubal ligation), etc.

Exclusion Criteria:

Patients in Cohort B may not participate in this trial if any of the following criteria apply.

1. Patients with the following medication or treatment history:

   ① Donor lymphocyte infusion (DLI) within 4 weeks

   • Graft-versus-host-disease (GVHD) treatment within four weeks (In case of maintaining medication for post-treatment prophylaxis, the decision on the subject's participation in the clinical trial may be made after contacting and consulting with the Sponsor's Medical Monitor.)

     • Central nervous system (CNS) radiotherapy or intracerebrospinal antineoplastic therapy within eight weeks (However, intrathecal therapy for prophylaxis purposes is an exception) ④ Systemic salvage chemotherapy that includes TKI and blinatumomab for treatment of Philadelphia positive ALL within one week prior to Screening or five half-lives of the administered drug (whichever is shorter)

       • Any prior anti-CD19 treatment (with the exception of blinatumomab) ⑥ History of neurological toxicity ≥ Grade 4 or cytokine release syndrome (CRS) ≥ Grade 4 per CTCAE during prior anti-CD19 treatment

2. Patients with the following CNS abnormality:

   ① CNS-3 disease, defined by WBC ≥ 5/μL in CSF and confirmed presence of lymphoblast, with or without neurological symptoms

   ② CNS-3 disease, defined by WBC < 5/μL in CSF and confirmed presence of lymphoblast, with neurological symptoms (cases of CNS-1 disease without evidence of leukemia involvement in CSF and CNS-2 disease without neurological symptoms may be enrolled)

   ③ Current or prior history of CNS disorder, such as epilepsy/seizure, cerebrovascular ischemia/bleeding, dementia, cerebellar disorder, autoimmune disease with CNS invasion, posterior reversible encephalopathy syndrome (PRES) or cerebral edema

3. Burkitt's lymphoma/leukemia per WHO Classification or chronic myelogenous leukemia lymphoid blast crisis

4. Primary immunodeficiency

5. Hereditary diseases (e.g., Fanconi anemia, Kostmann syndrome, and Shwachman-Diamond syndrome) or other bone marrow failure syndromes

2. Common Exclusion Criteria

Subjects in Phase 1 study and Phase 2 study may not participate in this trial if any of the following criteria apply.

1. Patients with the following medical history:

   • History of malignancy with the following exceptions:

     • Basal cell or squamous cell skin cancer treated without relapse for at least three years prior to Screening

     • In-situ carcinoma of the cervix or breast treated without relapse for at least 3 years prior to Screening

     • Superficial bladder cancer treated without relapse for at least 3 years prior to Screening

     • A primary malignancy which has been completely resected and in complete remission for ≥ 5 years

       • Unstable angina and/or myocardial infarction within 12 months prior to Screening ③ Thromboembolic events, pulmonary embolism or bleeding diatheses within 6 months prior to Screening

         • Hypoxemia, clinically significant pleural effusion or clinically significant ECG findings within 6 months prior to Screening

2. Patients with the following concurrent disease at Screening:

   • Central nervous system (CNS) involvement by malignancy by magnetic resonance imaging (MRI) at Screening. However, for Cohort B, subjects with malignant tumor metastasis to the brain parenchyma confirmed by MRI scan.

     • Active infection with hepatitis B confirmed (HBsAg positive at Screening. But, in case of HBcAb IgG positive, the patient can be enrolled if he/she takes prophylactic anti-viral agent.)

       • Active infection with hepatitis C confirmed (HCV Ab tested positive at Screening. But, if screened negative for HCV RNA, the patient can be enrolled.) ④ Known human immunodeficiency virus (HIV) positive ⑤ Active neurological auto-immune or inflammatory disorder (e.g., Guillain Barre syndrome, amyotrophic lateral sclerosis) ⑥ Ventricular tachycardia and atrial fibrillation with rapid ventricular response not controlled (i.e., relapsed or symptomatic) with pharmacological treatment within three months prior to Screening

3. Showing rapid progression of study disease as per Investigator's discretion

4. Had major surgery requiring general anesthesia or mechanical ventilation within four weeks prior to Screening (for video-assisted thoracoscopic surgery (VATS) or open-and-closed (ONC) surgery, within two weeks prior to Screening)

5. Severe infection requiring anti-bacterial, anti-fungal or anti-viral medication or uncontrolled active infection at Screening

6. Use of other investigational medicinal products/devices within 4 weeks prior to Screening

7. Pregnant or lactating women

8. Hypersensitivity reaction to the ingredients of the Investigational Product

Other protocol-related inclusion/exclusion may apply.