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Study to Evaluate the Safety and Efficacy of Anti-CD38 CAR-T in Relapsed or Refractory Multiple Myeloma Patients

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ClinicalTrials.gov Identifier: NCT03464916
Recruitment Status : Recruiting
First Posted : March 14, 2018
Last Update Posted : June 27, 2018
Sponsor:
Information provided by (Responsible Party):
Sorrento Therapeutics, Inc.

Brief Summary:
The study is an open-label Phase 1 single dose-escalation safety study of CAR2 Anti-CD38 A2 CAR-T Cells in patients with Relapsed or Refractory Multiple Myeloma, who meet all other eligibility criteria.

Condition or disease Intervention/treatment Phase
Relapsed or Refractory Multiple Myeloma Biological: CAR2 Anti-CD38 A2 CAR-T Cells Phase 1

Detailed Description:
All subjects who received investigational CAR-T therapy will be included in the analyses and summaries of safety, efficacy, pharmacokinetic, and pharmacodynamic assessments.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Intervention Model: Sequential Assignment
Intervention Model Description: To determine DLT and MTD, the design uses a 3+3 rule-based design. Dose escalation is permitted between successive cohorts based upon a specified algorithm, using discrete dosage steps.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Open-Label, Dose-Escalation, Pharmacokinetic, and Pharmacodynamic Study of the Safety and Efficacy of CAR2 Anti-CD38 A2 CAR-T Cells in Patients With Relapsed or Refractory Multiple Myeloma
Actual Study Start Date : April 5, 2018
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : September 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
Experimental: CAR2 Anti-CD38 A2 CAR-T Cells
Relapsed or Refractory Multiple Myeloma
Biological: CAR2 Anti-CD38 A2 CAR-T Cells
Autologous IV infusion; dose-escalation




Primary Outcome Measures :
  1. Determine the MTD [ Time Frame: 28 days ]
    The MTD is assessed according to a 3+3 dose-escalation design by the occurrence of treatment-emergent dose-limiting toxicities during the 28-day Treatment Period in the dose-escalation phase of the study


Secondary Outcome Measures :
  1. Determine the CAR2 Anti-CD38 A2 CAR-T cell blood concentrations (Pharmacokinetic [PK] Profile) to evaluate the Cmax [ Time Frame: 28 days ]
    CAR2 Anti-CD38 A2 CAR-T cell blood concentrations will be measured at different time points during the 28-day treatment period to evaluate the maximum concentration (Cmax).

  2. Determine the CAR2 Anti-CD38 A2 CAR-T cell blood concentrations (Pharmacokinetic [PK] Profile) to evaluate the AUC [ Time Frame: 28 days ]
    CAR2 Anti-CD38 A2 CAR-T cell blood concentrations will be measured at different time points during the 28-day treatment period to evaluate the area under the curve (AUC).

  3. Evaluate the safety of Anti-CD38 A2 CAR-T cells in Patients with RRMM by incidence of treatment-emergent adverse events [ Time Frame: 6 months ]
    The evaluation of safety will be measured by an assessment of the incidence of treatment-emergent adverse events for each patient in the dose-escalation and expansion phases of the study.

  4. Assess preliminary efficacy by response rate in accordance with the modified International Myeloma Working Group (IMWG) criteria [ Time Frame: 6 months ]
    As a measure of activity, overall response rate will be assessed according to the modified International Myeloma Working Group (IMWG) criteria. Response will be assessed for each patient over a 6-month timeframe during both the dose-escalation and expansion phases of the protocol.

  5. Assess preliminary efficacy by depth of response in accordance with the modified International Myeloma Working Group (IMWG) criteria. [ Time Frame: 6 months ]
    As a measure of activity, depth of response (ie, category of response) will be assessed according to the modified International Myeloma Working Group (IMWG) criteria. This will be assessed for each patient over a 6-month timeframe during both the dose-escalation and expansion phases of the protocol.

  6. Assess preliminary efficacy by duration of response in accordance with the modified International Myeloma Working Group (IMWG) criteria. [ Time Frame: 6 months ]
    As a measure of activity, duration of response will be assessed according to the modified International Myeloma Working Group (IMWG) criteria. This will be assessed for each patient over a 6-month timeframe during both the dose-escalation and expansion phases of the protocol.

  7. Assess preliminary efficacy by progression-free survival. [ Time Frame: 6 months ]
    As a measure of activity, Progression-free survival (PFS) will be assessed. The events for the assessment of PFS are disease progression and death events. This time to event endpoint will be estimated using Kaplan-Meier methods. Point estimates and 95% confidence intervals will be provided where appropriate.

  8. Assess preliminary efficacy by overall survival. [ Time Frame: 6 months ]
    As a measure of activity, Overall Survival (OS) will be assessed. The events for the assessment of OS are death events. Time to event endpoints will be estimated using Kaplan-Meier methods. Point estimates and 95% confidence intervals will be provided where appropriate.

  9. The determination of the recommended phase 2 dose (RP2D) will be based on an evaluation of treatment-emergent events. [ Time Frame: 6 months ]
    The RP2D will be assessed by the incidence of treatment-emergent adverse events during the Treatment and Observation Periods.

  10. The determination of the recommended phase 2 dose will be based on an evaluation of overall response rate. [ Time Frame: 6 months ]
    The rate of response as a determination factor for the RP2D will be assessed by the incidence of responses of at least partial response according to the IMWG criteria during the Treatment and Observation Periods.

  11. The determination of the recommended phase 2 dose (RP2D) will be based on an evaluation of depth of response. [ Time Frame: 6 months ]
    The depth of response as a determination factor for the RP2D will be assessed by the IMWG categories for response according to changes from baseline in M-protein levels in serum and urine, per cent plasma cells in the bone marrow, and size (area) of soft tissue extramedullary plasmacytomas (if applicable). This will be assessed for each patient over a 6-month timeframe during both the dose-escalation and expansion phases of the protocol.

  12. The determination of the recommended phase 2 dose (RP2D) will be based on an evaluation of duration of response. [ Time Frame: 6 months ]
    The duration of response as a determination factor for the RP2D will be assessed by the IMWG criteria for disease progression following the achievement of a response of at least a partial response according to changes in M-protein levels in serum and urine, per cent plasma cells in the bone marrow, the appearance of new lytic bone lesions, and/or the development of new soft tissue extramedullary plasmacytomas during the Treatment and Observation periods.

  13. The determination of the recommended phase 2 dose (RP2D) will be based on an evaluation of progression-free survival. [ Time Frame: 6 months ]
    Progression-free survival as a determination factor for the RP2D will be assessed by the IMWG criteria for disease progression events and death events. This time to event endpoint will be estimated using Kaplan-Meier methods. Point estimates and 95% confidence intervals will be provided where appropriate. Progression-free survival will be evaluated during the Treatment and Observation Periods of the study.

  14. The determination of the recommended phase 2 dose (RP2D) will be based on an evaluation of overall survival. [ Time Frame: 6 months ]
    Overall survival as a determination factor for the RP2D will be assessed by death events that occur during the Treatment and Observation Periods. Time- to-event endpoints will be estimated using Kaplan-Meier methods. Point estimates and 95% confidence intervals will be provided where appropriate.


Other Outcome Measures:
  1. An assessment of pharmacodynamics will be based on determining if there is an association of the achievement of at least a partial response with the level of Cmax of circulating CAR-T cells. [ Time Frame: 6 months ]
    The Cmax of the concentration of circulating CAR2 anti-CD38 CAR-T cells will be determined during the Treatment Period for each patient. The achievement of at least a partial response for each patient will be assessed during both the Treatment and Observation Periods for each patient. An analysis to determine if a specific level of Cmax for the circulating CAR2 anti-CD38 CAR-T cells obtained during the Treatment Period is required for patients to achieve at least a partial response during the Treatment and Observation Periods.

  2. An assessment of pharmacodynamics will be based on determining if there is an association of the achievement of at least a partial response with the AUC of circulating CAR-T cells. [ Time Frame: 6 months ]
    The AUC of circulating CAR2 anti-CD38 CAR-T cells will be determined during the Treatment Period for each patient. The achievement of at least a partial response for each patient will be assessed during both the Treatment and Observation Periods for each patient. An analysis to determine if a specific value for the AUC of circulating CAR2 anti-CD38 CAR-T cells obtained during the Treatment Period is required for patients to achieve at least a partial response during the Treatment and Observation Periods.

  3. An assessment of pharmacodynamics will be based on determining if there is an association of the incidence of at least Grade 3 cytokine release syndrome (CRS) adverse events with the level of Cmax of circulating CAR-T cells. [ Time Frame: 6 months ]
    The Cmax of the concentration of circulating CAR2 anti-CD38 CAR-T cells will be determined during the Treatment Period for each patient. The incidence of CRS adverse events for each patient will be assessed during both the Treatment and Observation Periods for each patient. An analysis will be conducted to determine if there is a level of Cmax for circulating CAR2 anti-CD38 CAR-T cells obtained during the Treatment Period above which is associated with the development of at least Grade 3 CRS in patients during the Treatment and Observation Periods.

  4. An assessment of pharmacodynamics will be based on determining if there is an association of the incidence of at least Grade 3 CRS with the AUC of circulating CAR-T cells. [ Time Frame: 6 months ]
    The AUC of circulating CAR2 anti-CD38 CAR-T cells will be determined during the Treatment Period for each patient. The incidence of at least Grade 3 CRS for each patient will be assessed during both the Treatment and Observation Periods for each patient. An analysis to determine if there is a specific value for the AUC of circulating CAR2 anti-CD38 CAR-T cells obtained during the Treatment Period above which is associated with the development of at least Grade 3 CRS in patients during the Treatment and Observation Periods.

  5. An assessment of pharmacodynamics will be based on determining if there is an association of the incidence of at least Grade 2 neurotoxicity adverse events with the level of Cmax of circulating CAR-T cells. [ Time Frame: 6 months ]
    The Cmax of the concentration of circulating CAR2 anti-CD38 CAR-T cells will be determined during the Treatment Period for each patient. The incidence of neurotoxicity adverse events for each patient will be assessed during both the Treatment and Observation Periods for each patient. An analysis will be conducted to determine if there is a level of Cmax for circulating CAR2 anti-CD38 CAR-T cells obtained during the Treatment Period above which is associated with the development of at least Grade 2 neurotoxicity adverse events in patients during the Treatment and Observation Periods.

  6. An assessment of pharmacodynamics will be based on determining if there is an association of the incidence of at least Grade 2 neurotoxicity adverse events with the AUC of circulating CAR-T cells. [ Time Frame: 6 months ]
    The AUC of circulating CAR2 anti-CD38 CAR-T cells will be determined during the Treatment Period for each patient. The incidence of at least Grade 2 neurotoxicity adverse events for each patient will be assessed during both the Treatment and Observation Periods for each patient. An analysis to determine if there is a specific value for the AUC of circulating CAR2 anti-CD38 CAR-T cells obtained during the Treatment Period above which is associated with the development of at least Grade 2 neurotoxicity adverse events in patients during the Treatment and Observation Periods.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must have RRMM after receiving greater than or equal to 3 lines of therapy and relapsed within 1 year of 1st/2nd line treatment
  • Must have evaluable disease
  • Must have a life expectancy of at least 12 weeks
  • Subjects should be willing and able to comply with the study schedule and protocols
  • Females of childbearing potential must have 2 negative pregnancy tests, agree to ongoing pregnancy testing during the study, and sexually active female and male subjects must be willing to use an effective method to avoid pregnancies.

Exclusion Criteria:

  • Subjects who received anticancer therapy or investigational drug within 28 days of first dose
  • Subjects who received any approved anticancer chemotherapy within 21 days of first dose (exception cyclophosphamide as NMA conditioning)
  • Subjects with unresolved toxicity greater than Grade 2 from previous therapies
  • Has a history of brain metastasis or spinal cord compression
  • Subjects with an ECOG performance status greater than or equal to 3
  • Has received allogenic hematopoietic stem cell transplantation (HSCT) within 6 months, have active graft-versus-host disease (GVHD) following transplant, or receiving immunosuppressive therapy following a transplant
  • Has received any CAR cell line therapies
  • Has any clinically significant low baseline lab results for hemoglobin, platelet counts, and neutrophil counts, at screening unless resulting from underlying RRMM.
  • Has any clinically significant elevated baseline lab results for serum creatinine, AST, and total bilirubin (except for patients in whom hyperbilirubinemia is attributed to Gilbert's syndrome) at screening regardless of causality.
  • Known HIV or acquired immunodeficiency syndrome-related illness, acute or history of chronic hepatitis B or C.
  • Female subjects who are pregnant or breastfeeding
  • Active bacterial, viral or fungal infections
  • Has plasma cell leukemia
  • Has medical condition, abnormality, or psychiatric illness that would prevent study participation
  • Left ventricular ejection fraction (LVEF) < 40%

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03464916


Contacts
Contact: Edward Stadtmauer, MD 215-662-7910 clinicaltrials@sorrentotherapeutics.com

Locations
United States, Pennsylvania
University of Pennsylvania, Abramson Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Harjeet K Sembhi, MPH    215-220-9688    harjeet.sembhi@uphs.upenn.edu   
Principal Investigator: Edward Stadtmauer, MD         
Sub-Investigator: Adam Cohen, MD         
Sub-Investigator: Dan Vogl, MD         
Sub-Investigator: Alfred Garfall, MD         
United States, Rhode Island
Roger Williams Medical Center Recruiting
Providence, Rhode Island, United States, 02908
Contact: Steven C Katz, MD    401-456-2484    skatz@CharterCARE.org   
Sponsors and Collaborators
Sorrento Therapeutics, Inc.
Investigators
Principal Investigator: Edward Stadtmauer, MD University of Pennsylvania

Responsible Party: Sorrento Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03464916     History of Changes
Other Study ID Numbers: SOR-CART-MM-001
First Posted: March 14, 2018    Key Record Dates
Last Update Posted: June 27, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sorrento Therapeutics, Inc.:
CAR2 Anti-CD38 A2 CAR-T Cells

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases