A Study Comparing JNJ-68284528, a CAR-T Therapy Directed Against B-cell Maturation Antigen (BCMA), Versus Pomalidomide, Bortezomib and Dexamethasone (PVd) or Daratumumab, Pomalidomide and Dexamethasone (DPd) in Participants With Relapsed and Lenalidomide-Refractory Multiple Myeloma

Multiple Myeloma Clinical Trial

— CARTITUDE-4  

Official title:

A Phase 3 Randomized Study Comparing JNJ-68284528, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against BCMA, Versus Pomalidomide, Bortezomib and Dexamethasone (PVd) or Daratumumab, Pomalidomide and Dexamethasone (DPd) in Subjects With Relapsed and Lenalidomide-Refractory Multiple Myeloma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04181827
• Other study ID #: CR108695
• Secondary ID: 2019-001413-1668
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 12, 2020
• Est. completion date: June 30, 2027

Study information

• Verified date: June 2024
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to compare the efficacy of JNJ-68284528 (ciltacabtagene autoleucel [cilta-cel]) with standard therapy, either Pomalidomide, Bortezomib and Dexamethasone (PVd) or Daratumumab, Pomalidomide and Dexamethasone (DPd).

Description:

Multiple myeloma is a malignant plasma cell disorder diagnosed annually in approximately 86,000 participants worldwide. JNJ-68284528 (cilta-cel) is an autologous chimeric antigen receptor T-cell (CAR-T) therapy that targets B-cell maturation antigen (BCMA), a molecule expressed on the surface of mature B lymphocytes and malignant plasma cells. The primary hypothesis for this study is that JNJ-68284528 (cilta-cel) will significantly improve progression free survival (PFS) compared with standard therapy (PVd or DPd), in participants who have previously received 1 to 3 prior line(s) of therapy, that included a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) and who are refractory to lenalidomide. This study will be conducted in 3 phases: Screening (up to 28 days before randomization), Treatment, and Follow-Up. Assessment like patient-reported outcome(s) (PROs) assessments, electrocardiogram (ECG), vital signs, pharmacokinetic will be performed during the study. Safety evaluations will include review of adverse events, laboratory test results, vital sign measurements, physical examination findings, and assessments of cardiac function, Immune Effector Cell-associated Encephalopathy (only for Arm B) and Eastern Cooperative Oncology Group performance status. Safety data will be periodically reviewed by an Independent Data Monitoring Committee (IDMC). The duration of the study is approximately 6 years.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 419
• Est. completion date: June 30, 2027
• Est. primary completion date: May 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Measurable disease at screening as defined by any of the following: (a) Serum monoclonal paraprotein (M-protein) level greater than or equal to (>=) 0.5 gram per deciliter (g/dL) or urine M-protein level >=200 milligram (mg)/24 hours; or (b) Light chain multiple myeloma without measurable M-protein in the serum or the urine: Serum free light chain >=10 mg/dL and abnormal serum free light chain ratio

• Have received 1 to 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD)

• Have documented evidence of PD by International Myeloma Working Group (IMWG) criteria based on investigator's determination on or within 6 months of their last regimen

• Be refractory to lenalidomide per IMWG consensus guidelines (failure to achieve minimal response or progression on or within 60 days of completing lenalidomide therapy). Progression on or within 60 days of the last dose of lenalidomide given as maintenance will meet this criterion. For participants with more than 1 prior line of therapy, there is no requirement to be lenalidomide refractory to the most recent line of prior therapy. However, participants must be refractory to lenalidomide in at least one prior line

• Have clinical laboratory values meeting the following criteria during the Screening Phase (re testing is allowed but the below criteria must be met in the latest test prior to randomization):

1. Hemoglobin >=8 gram per deciliter (g/dL) (without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted);

2. Absolute neutrophil count (ANC) >=1 * 10^9 per liter (L) (without recombinant human granulocyte colony-stimulating factor [G-CSF] within 7 days and without pegylated G-CSF within 14 days of the laboratory test);

3. Platelet count >=75 * 10^9/L (without prior platelet transfusion within 7 days before the laboratory test) in participants in whom less than (<) 50 percent (%) of bone marrow nucleated cells are plasma cells; platelet count >=50 * 10^9/L (without prior platelet transfusion within 7 days before the laboratory test) in participants in whom >=50% of bone marrow nucleated cells are plasma cells;

4. Lymphocyte count >=0.3 * 10^9/L;

5. Aspartate aminotransferase (AST) less than or equal to (<=)3 * upper limit of normal (ULN);

6. Alanine aminotransferase (ALT) <=3 * ULN;

7. Total bilirubin <=2.0 * ULN; except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin <=1.5 * ULN is required);

8. Estimated glomerular filtration rate >=40 milliliter per minute (mL/min) per 1.73 meter square (m^2) (to be calculated using the Modification of Diet in Renal Disease [MDRD] formula)

Exclusion Criteria:

• Prior treatment with chimeric antigen receptor T-cell (CAR-T) therapy directed at any target

• Any previous therapy that is targeted to B-cell maturation antigen (BCMA)

• Ongoing toxicity from previous anticancer therapy that has not resolved to baseline levels or to Grade 1 or less; except for alopecia

• Participants with Grade 1 peripheral neuropathy with pain or Grade 2 or higher peripheral neuropathy will not be permitted to receive pomalidomide, bortezomib, and dexamethasone (PVd) as standard therapy or bridging therapy; however, participants may receive daratumumab, pomalidomide, and dexamethasone (DPd) as standard therapy or bridging therapy

• Received a cumulative dose of corticosteroids equivalent to >=70 mg of prednisone within the 7 days prior to randomization

• Monoclonal antibody treatment within 21 days

• Cytotoxic therapy within 14 days

• Proteasome inhibitor therapy within 14 days

• Immunomodulatory drug (IMiD) therapy within 7 days

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• JNJ-68284528
Cilta-cel infusion will be administered at a target dose of 0.75 * 10^6 CAR-positive viable T cells/kilogram (kg).
• Pomalidomide
Pomalidomide 4 mg will be administered orally.
• Bortezomib
Bortezomib 1.3 milligram per meter square (mg/m^2) will be administered subcutaneously (SC).
• Dexamethasone
Dexamethasone 20 mg/day (10mg/day for participants >75 years of age) (on bortezomib treatment days and the days following bortezomib treatment) will be administered orally in PVd treatment; and orally or intravenous (IV) at 40 mg weekly (20mg weekly for participants >75 years of age) in DPd treatment.
• Daratumumab
Daratumumab 1800 mg will be administered SC.

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide
Australia	Royal Prince Alfred Hospital	Camperdown
Australia	Royal Brisbane and Womens Hospital	Herston
Australia	Alfred Health	Melbourne
Australia	Peter MacCallum Cancer Centre	Melbourne
Australia	Fiona Stanley Hospital	Murdoch
Belgium	Universitair Ziekenhuis - Antwerpen	Antwerp
Belgium	UZ Gent	Gent
Belgium	UZ Leuven	Leuven
Belgium	Centre Hospitalier Universitaire de Liege Domaine Universitaire du Sart Tilman	Liege
Denmark	Rigshospitalet	Copenhagen
France	CHRU de Lille Hopital Claude Huriez	LILLE Cedex
France	CHU de Montpellier, Hopital Saint-Eloi	Montpellier
France	C.H.U. Hotel Dieu - France	Nantes
France	Hopital Saint Louis	Paris cedex 10
France	Centre hospitalier Lyon-Sud	Pierre Benite cedex
France	CHU De Poitiers	Poitiers
France	Institut Universitaire du cancer de Toulouse-Oncopole	Toulouse cedex 9
Germany	Universitatsklinikum Carl Gustvav Carus Dresden an der Technischen Universitat Dresden	Dresden
Germany	Universitaetsklinikum Hamburg Eppendorf	Hamburg
Germany	Universitaetsklinikum Koeln	Koeln
Germany	Universitaetsklinikum Leipzig	Leipzig
Germany	Klinikum der Eberhard Karls Universitaet Abt fur innere Med II Haematologie Onkologie Germany	Tubingen
Germany	Universitatsklinikum Wurzburg	Wuerzburg
Greece	Attikon University General Hospital of Attica	Athens
Israel	Hadassah University Hospita Ein Kerem	Jerusalem
Israel	Sheba Medical Center	Ramat Gan
Israel	Sourasky Medical Center	Tel-Aviv
Italy	Azienda Opedaliero-Universitaria Policlinico Sant'orsola Malpighi di Bologna	Bologna
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano
Italy	IRCCS Ospedale San Raffaele HSR	Milano
Italy	Policlinico Universitario Agostino Gemelli	Roma
Italy	A.O.U. Citta della Salute e della Scienza di Torino - Presidio Molinette	Turin
Japan	Kyushu University Hospital	Fukuoka
Japan	Kanazawa University Hospital	Kanazawa
Japan	University Hospital Kyoto Perfectural University of Medicine	Kyoto
Japan	Nagoya City University Hospital	Nagoya
Japan	Okayama University Hospital	Okayama
Japan	Hokkaido University Hospital	Sapporo
Japan	Tohoku University Hospital	Sendai
Japan	Japanese Red Cross Medical Center	Shibuya
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	The Catholic University of Korea Seoul St. Mary's Hospital	Seoul
Netherlands	VU Medisch Centrum	Amsterdam
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Erasmus MC	Rotterdam
Netherlands	UMC Utrecht	Utrecht
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk
Poland	Narodowy Instytut Onkologii im.Marii Sklodowskiej Curie Panstwowy Instytut BadawczyOddz. w Gliwicach	Gliwice
Poland	Uniwersytecki Szpital Kliniczny w Poznaniu	Poznan
Poland	Instytut Hematologii i Transfuzjologii	Warszawa
Spain	Inst. Cat. D'Oncologia-Badalona	Badalona
Spain	Hosp Clinic de Barcelona	Barcelona
Spain	Hosp. Gral. Univ. Gregorio Maranon	Madrid
Spain	Hosp. Univ. 12 de Octubre	Madrid
Spain	Clinica Univ. de Navarra	Pamplona
Spain	Hosp Clinico Univ de Salamanca	Salamanca
Spain	Hosp. Virgen Del Rocio	Sevilla
Sweden	Skane University Hospital	Lund
Sweden	Karolinska Universitetssjukhuset Huddinge, Hematologiska Kliniken, Huddinge	Stockholm
Sweden	Akademiska Sjukhuset	Uppsala
United Kingdom	Queen Elizabeth Hospital	Birmingham
United Kingdom	Bristol Haematology and Oncology Centre	Bristol
United Kingdom	University Hospital Wales	Cardiff
United Kingdom	King s College Hospital	London
United Kingdom	University College Hospital	London
United Kingdom	Christie Hospital	Manchester
United Kingdom	Freeman Hospital	Newcastle Upon Tyne
United States	University Of Maryland Medical Center	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	The Ohio State University	Columbus	Ohio
United States	Colorado Blood Cancer Institute	Denver	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	University of Iowa Hospitals & Clinics	Iowa City	Iowa
United States	Wisconsin Institutes for Medical Research	Madison	Wisconsin
United States	University of Miami Leonard M. Miller School of Medicine - SCCC	Miami	Florida
United States	Medical College Of Wisconsin	Milwaukee	Wisconsin
United States	Yale New Haven Hospital	New Haven	Connecticut
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Mayo Clinic Cancer Center-Scottsdale	Phoenix	Arizona
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	University of Rochester Medical Center	Rochester	New York
United States	Washington University School Of Medicine	Saint Louis	Missouri
United States	Huntsman Cancer Institute	Salt Lake City	Utah
United States	Stanford University Medical Center	Stanford	California
United States	University of Kansas	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Denmark,  France,  Germany,  Greece,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Poland,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS)	PFS is defined as the time from the date of randomization to the date of first documented disease progression as defined in the IMWG criteria, or death due to any cause, whichever occurs first.	Until end of the study (up to 6 years)
Secondary	Complete Response (CR) or Stringent Complete Response (sCR) Rate	CR or sCR rate is defined as percentage of participants who achieve a CR or sCR response according to the International Myeloma Working Group (IMWG) criteria.	Until end of the study (up to 6 years)
Secondary	Overall Minimal Residual Disease (MRD) Negative Rate	Overall MRD negativity is defined as the percentage of participants who achieve MRD negativity at any time after the date of randomization before initiation of subsequent therapy.	Until end of the study (up to 6 years)
Secondary	MRD Negativity Rate in Participants with CR or sCR at 12 Months +/-3 Months	MRD negativity rate in participants with CR or sCR at 12 months +/-3 months is defined as the percentage of participants who achieve MRD-negative status and are in CR or sCR within time window.	Until end of the study (up to 6 years)
Secondary	Sustained MRD Negative Rate	Sustained MRD negativity rate is defined as the percentage of participants who achieve MRD negativity, confirmed minimum 1 year apart and without any examination showing MRD positive status in between.	Until end of the study (up to 6 years)
Secondary	Overall Survival (OS)	OS is measured from the date of randomization to the date of the participant's death. If the participant is alive or the vital status is unknown, then the participant's data will be censored at the date the participant was last known to be alive.	Until end of the study (up to 6 years)
Secondary	Overall response rate (ORR)	ORR is defined as the percentage of participants who achieve a partial response (PR) or better according to the IMWG criteria.	Until end of the study (up to 6 years)
Secondary	Time to Worsening of Symptoms	Time to worsening of symptoms is measured as the interval from the date of randomization to the start date of worsening in the Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q) total symptom score. The MySIm-Q is a disease-specific PRO assessment complementary to the EORTC-QLQ-C30. It includes 17 items resulting in a symptom subscale and an impact subscale. The recall period is the "past 7 days" and responses are reported on a 5 point verbal rating scale.	Until end of the study (up to 6 years)
Secondary	Progression Free Survival on next-line therapy (PFS2)	PFS2 is defined as the time interval between the date of randomization and date of event, which is defined as progressive disease as assessed by investigator that starts after the next line of subsequent therapy, or death from any cause, whichever occurs first.	Until end of the study (up to 6 years)
Secondary	Incidence and Severity of Adverse Events (AEs)	Incidence and severity of AEs will be reported.	Until end of the study (up to 6 years)
Secondary	Systemic Cytokine Concentrations	Serum or plasma proteomic profiling of cytokines (such as interleukin [IL] 6, IL-15, and IL 10) concentrations will be measured for biomarker assessment.	Until end of the study (up to 6 years)
Secondary	Levels of CAR-T Cell Activation Markers	CAR-T cell activation markers including, but not limited to, CD4+, CD8+, CD25+, central memory, effector memory cells will be reported. An evaluation of cell populations may be performed by flow cytometry or cytometry by time of flight (CyTOF) or both and correlated with response.	Until end of the study (up to 6 years)
Secondary	Levels of JNJ-68284528 T Cell Expansion (proliferation), and Persistence	Levels of JNJ-68284528 T cell expansion (proliferation), and persistence via monitoring CAR-T positive cell counts and CAR transgene level will be reported.	Until end of the study (up to 6 years)
Secondary	Number of Participants with Anti-JNJ-68284528 Antibodies	Number of participants exhibiting anti-drug antibodies for JNJ-68284528 will be reported.	Until end of the study (up to 6 years)
Secondary	Change from Baseline in Health-Related Quality of Life (HRQoL) as Assessed by European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC-QLQ-C30) Scale Score	The EORTC QLQ-C30 includes 30 items in 5 functional scales, 1 global health status scale, 3 symptom scales, and 6 single symptom items. The responses are reported using a verbal rating scale. The item and scale scores are transformed to a 0 to 100 scale. A higher score represents greater HRQoL, better functioning, and more (worse) symptoms.	Until end of the study (up to 6 years)
Secondary	Change from Baseline in Health-Related Quality of Life as Assessed by MySIm-Q Scale Sore	The MySIm-Q is a disease-specific PRO assessment complementary to the EORTC-QLQ-C30. It includes 17 items resulting in a symptom subscale and an impact subscale. The recall period is the "past 7 days" and responses are reported on a 5 point verbal rating scale.	Until end of the study (up to 6 years)
Secondary	Change from Baseline in Health-Related Quality of Life as Assessed by European Quality of Life - 5 Dimensions-5 Levels (EQ-5D-5L) Scale Score	The EQ-5D-5L is a generic measure of health status. The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating "health today" with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).	Until end of the study (up to 6 years)
Secondary	Change from Baseline in Health-Related Quality of Life as Assessed by Patient Global Impression of Symptom Severity (PGIS) Scale Score	The PGIS is a single item to assess the participant's perception in the severity of their overall health status using a 5-point verbal rating scale. Score ranges from 1 (None) to 5 (Very Severe).	Until end of the study (up to 6 years)
Secondary	Frequency in Health-Related Quality of Life as Assessed by The Patient-reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Item	Frequency distributions of the PRO-CTCAE is an item library of common adverse events experienced by people with cancer that are appropriate for self-reporting. Each symptom selected for inclusion can be rated by up to 3 attributes characterizing the presence/frequency, severity, and/or interference of the adverse event. A 5-point verbal rating scale is used for participants to select their experience based on the last 7 days.	Until end of the study (up to 6 years)