CLINICAL DATA - CARTITUDE-1 - PHASE 1B/2 STUDY

CARTITUDE-1 (MMY2001; clinicaltrials.gov identifier: NCT03548207) was a phase 1b/2, open-label, single-arm, multicenter study that evaluated the safety and efficacy of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) in patients with relapsed/refractory multiple myeloma (RRMM) who had previously received a protease inhibitor (PI), an immunomodulatory agent, and an anti-CD38 antibody. The combined analysis from the phase 1b/2 portions of the CARTITUDE-1 study evaluated the safety and efficacy of CARVYKTI in 97 patients with RRMM.^1,2

Study Design/Methods

CARTITUDE-1 Study Protocol - Eligibility Criteria for Lymphodepleting Regimen

Patients had to meet the following criteria to proceed with cyclophosphamide and fludarabine dosing:

• Echocardiogram or multiple-gated acquisition (MUGA) scan for patients who receive bridging therapy, including agents with known cardiac toxicity but not limited to anthracyclines and carfilzomib (per prescribing information), and verification of nonimpaired cardiac function (left ventricular ejection fraction [LVEF] ≥45%) should be performed after completion of bridging therapy and before the first dose of the lymphodepleting regimen.³
• No new arrhythmia or other cardiac adverse events unless controlled with medical management and approved by the treating healthcare provider.³
• Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1.³
• No active grade 3 toxicity with any bridging therapy and washout from bridging therapy should be completed.³
• No antitumor therapy within timeframe presented below; washout from bridging therapy completed as specified (no prior antitumor therapy as follows, prior to apheresis):³
  • Targeted therapy, epigenetic therapy, or treatment with an investigational drug or used an invasive investigational medical device within 14 days or at least 5 halflives, whichever is less.³
  • Monoclonal antibody treatment for multiple myeloma (MM) within 21 days³
  • Cytotoxic therapy within 14 days³
  • PI within 14 days, or an immunomodulatory agent within 7 days³
  • Radiotherapy within 14 days. However, patients were eligible irrespective of the end date of radiotherapy if the radiation portal covered ≤5% of the bone marrow reserve.³
• Transfusion support was allowed to maintain a hemoglobin ≥8.0 g/dl (≥5 mmol/L) as needed, and platelets ≥50.0×10⁹/L until 3 days before the hematology laboratory test, preceding lymphodepletion. Myeloid growth factors were permitted up to 1 day before the start of the lymphodepleting regimen. Pegylated myeloid growth factors (ie, pegfilgrastim) were prohibited.³
• No cumulative dose of corticosteroids equivalent to ≥70 mg prednisone within the 7 days before lymphodepleting regimen dosing. The sponsor should approve if a patient receives corticosteroids >10 mg/day in the week before the first dose of the lymphodepleting regimen.³
• No signs of active infection. For patients requiring systemic anti-microbial treatment or with temperature ≥38.0°C within 7 days before the first dose of the lymphodepleting regimen, the investigator should receive approval from the sponsor.³
• No major surgery ≤2 weeks before the first dose of lymphodepleting regimen.³
• No live, attenuated vaccines within 4 weeks before the first dose of the lymphodepleting regimen.³
• No supplemental oxygen use to maintain adequate oxygenation.³
• Negative pregnancy test for women of childbearing potential up to 72 hours before the first dose of the lymphodepleting regimen.³
• Patients should be evaluated for the presence of an indwelling catheter before the first dose of the lymphodepleting regimen.³
• Clinical laboratory values required for enrollment are presented in Table: CARTITUDE-1: Clinical Laboratory Values Required for Enrollment.

Cyclophosphamide and Fludarabine Lymphodepleting Regimen

• After successful manufacturing and quality testing of the CARVYKTI product, patients underwent lymphodepletion with cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² intravenously (IV) daily for 3 days on days -5 to -3.^1,3
• Per CARTITUDE-1 Study Protocol:
  • The dose of fludarabine should have been reduced to 24 mg/m² for patients with an estimated glomerular filtration rate (eGFR) of 30 to 70 mL/min/1.73m². Sponsor approval must have been obtained to modify the lymphodepleting/conditioning regimen schedule or dose.³
  • If administration of cyclophosphamide and fludarabine was delayed ≥10 weeks after apheresis, the patient must have undergone full rescreening before dosing. Cyclophosphamide and fludarabine should have been administered using administration procedures and supportive care according to the site’s standard of care.³
• Patients received a single infusion of CARVYKTI at a target dose 0.75×10⁶ chimeric antigen receptor+ (CAR+) T cells/kg (target range 0.5-1.0×10⁶) 5-7 days after the start of lymphodepleting regimen.¹
• Among the 113 patients enrolled/apheresed, 101 patients were lymphodepleted, and
  97 patients were treated with CARVYKTI infusion.¹
  • Four patients discontinued between lymphodepletion and CARVYKTI infusion (3 patients withdrew; 1 patient death due to respiratory failure).¹

CARTITUDE-1 Study Protocol - Evaluation Prior to Administration of CARVYKTI

• CARVYKTI dosing delays:
  • Patients were evaluated for safety on the day of CARVYKTI infusion to assess any significant change in health status (eg, clinical deterioration, rapidly progressing disease) after the start of the lymphodepleting regimen.³
• CARVYKTI infusion was delayed if any of the following events occurred:
  • Signs of active infection.³
    • CARVYKTI should not be administered to patients with active infection.³
    • For patients requiring systemic anti-microbial treatment, or with temperature ≥38°C within 48 hours before CARVYKTI infusion, investigator must consult with the sponsor prior to dosing.³
  • Grade ≥3 non-hematologic toxicities of cyclophosphamide and fludarabine lymphodepletion (except for grade 3 nausea, vomiting, diarrhea, or constipation). Investigator must consult with the sponsor prior to dosing.³
  • If resolution of these events to grade ≤1 requires more than 14 days, the lymphodepleting regimen should be re-administered after a minimum of 21 days following the first dose of the first lymphodepleting regimen.³

CLINICAL DATA - CARTITUDE-4 - PHASE 3 STUDY

CARTITUDE-4 (MMY3002; clinicaltrials.gov identifier: NCT04181827) is an ongoing, phase 3, randomized, open-label study evaluating the efficacy and safety of CARVYKTI vs standard care (physician’s choice of pomalidomide, bortezomib, and dexamethasone [PVd] or DARZALEX FASPRO [daratumumab and hyaluronidase], pomalidomide, and dexamethasone [DPd]) in adult patients with lenalidomide-refractory MM after 1-3 prior lines of therapy.^4,5

Study Design/Methods

CARTITUDE-4 Study Protocol - Eligibility Criteria for Lymphodepleting Regimen

Patients had to meet the following criteria to proceed with cyclophosphamide and fludarabine dosing⁶:

• Transfusion support was permitted to maintain a hemoglobin level of ≥8 g/dL, as needed, and a platelet count of ≥50×10⁹/L until 3 days before the hematology laboratory test preceding lymphodepletion.⁶
• Myeloid growth factors were permitted at the investigator’s discretion up to 1 day prior to the start of the lymphodepleting/conditioning regimen. Pegylated myeloid growth factors (ie, pegfilgrastim) were prohibited.⁶
• eGFR ≥30 mL/min/1.73 m². The dose of fludarabine was reduced according to the guidance in Section 6.1.5.3 of the CARTITUDE-4 study protocol.⁶
• The investigator was supposed to contact the sponsor if the patient had any signs of a reduction in kidney function, which may have manifested as a clinically significant increase in serum creatinine, a clinically significant decrease in eGFR, and/or a clinically significant decrease in urine output compared to baseline.⁶
• ECOG PS ≤1.⁶
• Negative pregnancy test for women of childbearing potential up to 72 hours before the first dose of the lymphodepleting regimen.⁶
• Patients should not have received the following prior to the start of the lymphodepleting/conditioning regimen⁶:
  • Daratumumab within 21 days
  • Bortezomib within 14 days
  • Pomalidomide within 7 days
  • Dexamethasone within 7 days
• No active non-hematologic grade ≥3 toxicity secondary to bridging therapy.⁶
• No live, attenuated vaccines within 6 weeks before the first dose of the lymphodepleting regimen.⁶
• No signs of infection. For patients requiring systemic anti-microbial treatment or with temperature >38.0°C within 7 days before the first dose of the lymphodepleting regimen, the investigator would receive approval from the sponsor.⁶
• No cumulative dose of corticosteroids equivalent to ≥70 mg prednisone within 7 days before the lymphodepleting regimen dosing. The sponsor would approve if a patient received corticosteroids at a dose equivalent to >10 mg prednisone per day in the week prior to the first dose of the lymphodepleting regimen.⁶
• No supplemental oxygen use to maintain adequate oxygenation.⁶
• No new arrhythmia or other cardiac adverse events unless controlled with medical management and approved by the medical monitor.⁶
• Clinical laboratory values required for enrollment are presented in Table: CARTITUDE-4: Clinical Laboratory Values Required for Enrollment.⁶

Cyclophosphamide and Fludarabine Lymphodepleting Regimen

• After completion of PVd or DPd bridging therapy and after the site was notified in writing by the sponsor that manufacture and quality testing of CARVYKTI had been completed, each patient received a lymphodepleting/conditioning regimen of cyclophosphamide IV 300 mg/m² and fludarabine 30 mg/m² daily for 3 days.⁶
• Per CARTITUDE-4 study protocol:
  • Sponsor approval was obtained to change the lymphodepleting/conditioning regimen schedule.⁶
  • The dose of fludarabine was reduced to 24 mg/m² for patients with an eGFR of 3070 mL/min/1.73 m².⁶
  • Cyclophosphamide and fludarabine were administered using administration procedures and supportive care according to the site’s standard of care.⁶
• Patients received a single infusion of CARVYKTI on day 1 at a target dose of 0.75x10⁶ CAR+ T cells/kg 5-7 days after the start of lymphodepletion.^4,6

CARTITUDE-4 Study Protocol - Evaluation Prior to Administration of CARVYKTI

• CARVYKTI dosing delays⁶:
  • Patients were evaluated for safety on the day of CARVYKTI infusion to assess any significant change in health status (eg, clinical deterioration, rapidly progressing disease) after the start of the lymphodepleting regimen.
• CARVYKTI infusion was delayed if any of the following events occurred⁶:
  • Signs of active infection
    • CARVYKTI should not be administered to patients with active infection.
    • For patients requiring systemic anti-microbial treatment or with temperature ≥38°C/100.4°F within 48 hours before CARVYKTI infusion, the investigator must consult with the sponsor prior to dosing.
  • Grade ≥3 non-hematologic toxicities of cyclophosphamide and fludarabine lymphodepletion (except for grade 3 nausea, vomiting, diarrhea, or constipation). The investigator must consult with the sponsor prior to dosing.
  • If resolution of these events to grade ≤1 requires more than 14 days, the lymphodepleting regimen should be re-administered after a minimum of 21 days following the first dose of the first lymphodepleting regimen.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 08 May 2024.