Clinical trial NCT04910568: A Study Evaluating the Safety, Pharmacokinetics, and Activity of Cevostamab in Participants With Relapsed or Refractory Multiple Myeloma
Official title: An Open-Label, Multicenter, Phase Ib Trial Evaluating the Safety, Pharmacokinetics, and Activity of Cevostamab as Monotherapy and Cevostamab Plus Pomalidomide and Dexamethasone or Cevostamab Plus Daratumumab and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Multiple Myeloma
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Hoffmann-La Roche
First posted: 2021-06-02
Enrollment: 126
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This Phase Ib, multicenter, open-label study will evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cevostamab monotherapy, cevostamab plus pomalidomide and dexamethasone (Pd) or cevostamab plus daratumumab and dexamethasone (Dd) which will be administered to participants with relapsed or refractory multiple myeloma (R/R MM) via intravenous (IV) infusion.


Eligibility criteria: Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
* Life expectancy of at least 12 weeks
* Agreement to provide bone marrow biopsy and aspirate samples
* Resolution of adverse events from prior anti-cancer therapy to Grade \<=1
* Measurable disease
* For women of childbearing potential: agreement to remain abstinent or use contraception, during the treatment period (including treatment interruptions) and for at least 5 months after the last dose of cevostamab and at least 3 months after the last dose of tocilizumab was administered
* For men: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm, during the treatment period, and for at least 2 months after the last dose of tocilizumab was administered to avoid exposing the embryo and sexual partner Additional Arm A-Specific Inclusion Criteria
* Diagnosis of R/R MM for which no established therapy for MM is appropriate and available, or intolerance to those established therapies Additional Arm B-Specific Inclusion Criteria
* For Cohort B1S: Participants with R/R MM who have received at least two prior lines of treatment
* For Cohort B2S and additional cohorts: Participants with R/R MM who have received at least 1 prior line of treatment
* Agreement to comply with all requirements of the pomalidomide pregnancy prevention program
* For women of childbearing potential: agreement to remain abstinent or use two reliable methods of contraception starting at least 4 weeks prior to, during the treatment period, and for at least 4 weeks after the last dose of pomalidomide was administered
* For men: agreement to remain abstinent or use a condom during the treatment period and for at least 4 weeks after the last dose of pomalidomide, (even if he has undergone a successful vasectomy) and agreement to refrain from donating sperm and blood during this same period Additional Arm C-Specific Inclusion Criteria
* For Cohort C1S: Participants with R/R MM who have received at least two prior lines of treatment
* For Cohort C2S and additional cohorts: Participants with R/R MM who have received at least 1 prior line of therapy
* For women of childbearing potential: agreement to remain abstinent or use contraceptive methods during the treatment period and for at least 102 days after the last dose of daratumumab was administered
* For men: agreement to remain abstinent or use a condom during the treatment period and for at least 102 days after the last dose of daratumumab was administered to avoid exposing the embryo, and agreement to refrain from donating sperm during this same period

Exclusion Criteria:

* Prior treatment with cevostamab or another agent targeting FcRH5
* Inability to comply with protocol-mandated hospitalization and activities restrictions
* Pregnant or breastfeeding, or intending to become pregnant during the study or within 5 months after the last dose of cevostamab or within 3 months after the last dose of tocilizumab (if applicable).
* Prior use of any monoclonal antibody, radioimmunoconjugate, or antibody-drugconjugate as anti-cancer therapy within 4 weeks before first study treatment, except for the use of non-myeloma therapy
* Prior treatment with systemic immunotherapeutic agents, including, but not limited to, cytokine therapy and anti-CTLA4, anti-PD-1, and antiPD-L1 therapeutic antibodies within 12 weeks or 5 half-lives of the drug, whichever is shorter, before first study treatment
* Prior treatment with chimeric antigen receptor T (CAR T)-cell therapy within 12 weeks before first study treatment
* Treatment with radiotherapy within 4 weeks (systemic radiation) or 14 days (focal radiation) prior to first study treatment
* Treatment with any chemotherapeutic agent or other anti-cancer agent (investigational or otherwise) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to first study treatment
* Autologous SCT within 100 days prior to first study treatment
* Prior allogeneic stem cell transplant(ation) (SCT)
* Circulating plasma cell count exceeding 500/micro L or 5% of the peripheral blood white cells
* Prior solid organ transplantation
* History of autoimmune disease
* History of confirmed progressive multifocal leukoencephalopathy
* History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
* Known history of amyloidosis
* Lesions in proximity of vital organs that may develop sudden decompensation/deterioration in the setting of a tumor flare
* History of other malignancy within 2 years prior to screening
* Known treatment-related, immune-mediated adverse events associated with prior checkpoint inhibitors
* Current or past history of central nervous system (CNS) disease, such as stroke, epilepsy, CNS vasculitis, neurodegenerative disease, or CNS involvement by MM
* Significant cardiovascular disease
* Symptomatic active pulmonary disease or requiring supplemental oxygen
* Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
* Known or suspected chronic active Epstein-Barr virus (EBV) infection
* Recent major surgery within 4 weeks prior to first study treatment
* Positive serologic or PCR test results for acute or chronic hepatitis B virus (HBV) infection
* Acute or chronic hepatitis C virus (HCV) infection
* Known history of Grade \>= 3 CRS or immune effector cell-associated neurotoxicity syndrome (ICANS) with prior bispecific therapies
* Known history of hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS)
* Active symptomatic coronavirus disease 2019 (COVID-19) infection at study enrollment or requiring treatment with intravenous (IV) antiviral where the last dose of IV antiviral treatment was given within 14 days prior to first study treatment. Patients with active COVID-19 infection must have clinical recovery and two negative antigen tests at least 24 hours apart prior to first study treatment
* Positive and quantifiable EBV polymerase chain reaction (PCR) or Cytomegalovirus (CMV) PCR prior to first study treatment
* Known history of HIV seropositivity
* Administration of a live, attenuated vaccine within 4 weeks before first study treatment or anticipation that such a live attenuated vaccine will be required during the study
* Treatment with systemic immunosuppressive medications, with the exception of corticosteroid treatment \<=10 mg/day prednisone or equivalent, within 2 weeks prior to first study treatment
* History of illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's judgment Additional Arm B-Specific Exclusion Criteria
* Pregnant or breastfeeding, or intending to become pregnant 4 weeks prior to initiation of study treatment, during the study, (including treatment interruptions) or within 4 weeks after the last dose of pomalidomide
* Significant cardiovascular disease (such as, but not limited to, New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 12 months, uncontrolled arrhythmias, or unstable angina)
* History of erythema multiforme, Grade \>=3 rash, blistering, or severe hypersensitivity to prior treatment with immunomodulatory drugs such as thalidomide, lenalidomide, or pomalidomide
* Inability to tolerate thromboprophylaxis, or contraindication to thromboprophylaxis
* GI disease that might significantly alter absorption of oral drugs Additional Arm C-Specific Exclusion Criteria
* Pregnant or breastfeeding, or intending to become pregnant during the study or within 102 days after the last dose of daratumumab
* Known hypersensitivity to biopharmaceuticals produced in CHO cells or any component of daratumumab formulations
* Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) \<50% of predicted normal
* Known moderate or severe persistent asthma within the past 2 years, or current uncontrolled asthma of any classification

Primary outcomes:
measure: Recommended Phase II Dose (RP2D)
timeFrame: Baseline up to approximately 4 years
measure: Percentage of Participants with Adverse Events
timeFrame: Baseline up to approximately 4 years
measure: Percentage of Dose Interruptions
timeFrame: Baseline up to approximately 4 years
measure: Percentage of Dose Reductions
timeFrame: Baseline up to approximately 4 years
measure: Percentage of Dose Intensity
timeFrame: Baseline up to approximately 4 years
measure: Percentage of Treatment Discontinuation
timeFrame: Baseline up to approximately 4 years
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Baseline up to approximately 4 years
measure: Complete Response/Stringent Complete Response (CR/sCR) Rate
timeFrame: Baseline up to approximately 4 years
measure: Rate of Very Good Partial Response (VGPR) or Better
timeFrame: Baseline up to approximately 4 years
measure: Progression-free Survival (PFS)
timeFrame: Start of study treatment to first date of disease progression or death from any cause, whichever occurs first (up to approximately 4 years)
measure: Duration of Response (DOR)
timeFrame: From first partial response (PR) or better until the first date of disease progression or death from any cause, whichever occurs first (up to approximately 4 years)
measure: Time to First Response (for Participants who Achieve a Response of Partial Response (PR) or Better)
timeFrame: Baseline up to approximately 4 years
measure: Time to Best Response (for Participants who Achieve a Response of PR or Better)
timeFrame: Baseline up to approximately 4 years
measure: Minimal Residual Disease (MRD) Negativity
timeFrame: Baseline up to approximately 4 years
measure: Overall Survival (OS)
timeFrame: Baseline up until death from any cause (up to approximately 4 years)
measure: Serum Concentration of Cevostamab at Specified Timepoints
timeFrame: Cevostamab Pre-Phase (CPP) Day (D) 1 up to approximately 3 years
measure: Total Exposure (Area Under the Concentration-time Curve [AUC]) of Cevostamab
timeFrame: CPP D1 up to approximately 4 years
measure: Maximum Observed Serum Concentration (Cmax) of Cevostamab
timeFrame: CPP D1 up to approximately 4 years
measure: Minimum Observed Serum Concentration (Cmin) of Cevostamab
timeFrame: CPP D1 up to approximately 4 years
measure: Clearance of Cevostamab
timeFrame: CPP D1 up to approximately 4 years
measure: Volume of Distribution at Steady State of Cevostamab
timeFrame: CPP D1 up to approximately 4 years
measure: Number of Anti-drug Antibody (ADAs) Against Cevostamab at Baseline
timeFrame: Baseline
measure: Percentage of Participants with ADAs Against Cevostamab During the Study
timeFrame: Up to approximately 4 years
measure: Serum Concentration of Pomalidomide
timeFrame: From Cycle 1 Day 1 through Cycle 6 Day 15. Each cycle=28 days
measure: Serum Concentration of Daratumumab
timeFrame: From C1D1 until disease progression or unexpected toxicity. Cycles 1-8 are 21 days and Cycle 9 onward are 28 days.
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Irvine
country: United States
facility: City of Hope - Lennar Foundation Cancer Center
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute (CBCI) at Presbyterian/ St. Luke's Medical Center
state: Colorado
city: Detroit
country: United States
facility: Karmanos Cancer Institute.
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Hamilton
country: Canada
facility: Hamilton Health Sciences
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Ostrava
country: Czechia
facility: Fakultni Nemocnice Ostrava
city: København Ø
country: Denmark
facility: Rigshospitalet
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Poitiers
country: France
facility: CHU de Poitiers - La Miletrie
city: Rennes
country: France
facility: CHU Pontchaillou
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Tel-Aviv
country: Israel
facility: Sourasky Medical Centre
city: Bergamo
country: Italy
facility: Asst Papa Giovanni Xxiii
state: Lombardia
city: Brescia
country: Italy
facility: A.O. Spedali Civili Di Brescia-P.O. Spedali Civili
state: Lombardia
city: Tokyo
country: Japan
facility: The Cancer Institute Hospital of JFCR
city: Yamagata
country: Japan
facility: Yamagata University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Gda?sk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Katowice
country: Poland
facility: Pratia Onkologia Katowice
city: Pozna?
country: Poland
facility: Uniwersytecki Szpital Kliniczny w Poznaniu
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital
Study officials:
affiliation: Genentech, Inc.
name: Clinical Trials
role: STUDY_DIRECTOR
References: