Clinical trial NCT03287908: A Study to Assess AMG 701 Montherapy, or in Combination With Pomalidomide, With or Without, Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma
Official title: A Phase 1/2 Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 701 Monotherapy, or in Combination With Pomalidomide, With and Without Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma (ParadigMM-1B)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Relapsed/Refractory Multiple Myeloma
Keywords: Amgen
Phase 1
Phase 2
Phase 1/2
Clinical Trial
Oncology/Hematology
Relapsed/Refractory Multiple Myeloma
Immunotherapy
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2017-09-19
Enrollment: 174
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The primary purpose of the phase 1 part of the study is to evaluate safety and tolerability of AMG 701 monotherapy to identify the RP2D for AMG 701 monotherapy followed by a dose-confirmation part to gather further safety data for AMG 701 monotherapy at the RP2D in adult subjects with relapsed/refractory multiple myeloma (RRMM). In addition, this study will include a sequential dose exploration part to identify the RP2D of AMG 701 in combination with pomalidomide, with and without dexamethasone (AMG 701-P+/-d). Phase 2 will consist of the dose-expansion part to gain further efficacy and safety experience with AMG 701 monotherapy in adult subjects with RRMM.


Eligibility criteria: Inclusion Criteria:

* Multiple myeloma meeting the following criteria:

  * Pathologically-documented diagnosis of multiple myeloma that is relapsed or is refractory as defined by the following:

    * Relapsed after \> or = 3 lines of prior therapy that must include all approved and available therapies deemed eligible by the investigator, inclusing at a minimum of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and, where approved and available, a CD38-directed cytolytic antibody in combination in the same line or separate lines of treatment OR refractory to PI, IMiD, and CD38- directed cytolytic antibody,
    * Subjects who could not tolerate a PI, IMiDs, or a CD38-directed cytolytic antibody are eligible to enroll in the study.
  * Measurable disease as per IMWG response criteria
* Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2

Inclusion criteria specific to AMG 701-P±d include:

* Subjects must have received ≥ 2 lines of prior therapy that must include a proteasome inhibitor (PI), lenalidomide, and where approved and available a CD38-directed antibody. These therapies may be in the same line or separate lines of treatment.
* Subjects must have responded to at least 1 prior line with at least a PR.
* Subjects that have previously received pomalidomide must not have been removed from therapy due to toxicity attributable to pomalidomide and must be at least 6 months from their last dose of pomalidomide.
* Subjects must not have known intolerance to doses of dexamethasone up to 40 mg weekly (20 mg weekly if \> 75 years).

Exclusion Criteria:

* Known extramedullary relapse in the absence of any measurable medullary involvement
* Known central nervous system involvement by multiple myeloma
* Autologous stem cell transplantation less than 90 days prior to study day 1
* Recent history of primary plasma cell leukemia (within last 6 months prior to enrollment) or evidence of primary or secondary plasma cell leukemia at the time of screening
* Waldenstrom's macroglobulinemia
* Prior amyloidosis (subjects with multiple myeloma with asymptomatic deposition of amyloid plaques found on biopsy would be eligible if all other criteria are met)
* Treatment with systemic immune modulators including, but not limited to, nontopical systemic corticosteroids (unless the dose is ≤ 10 mg/day prednisone or equivalent), cyclosporine, and tacrolimus within 2 weeks before study day 1
* Last anticancer treatment (chemotherapy, IMiD, PI, molecular targeted therapy) \< 2 weeks prior to study day 1 or treatment with a therapeutic antibody less than 4 weeks prior to study day 1 as well as systemic radiation therapy within 28 days prior to study day 1 or focal radiotherapy within 14 days prior to study day 1.
* Prior treatment with any drug or construct that targets BCMA on tumor cells (eg, other bispecific antibody constructs, antibody drug conjugates, or CAR-T cells), other than Group C where prior treatment with GSK2857916 (belantamab mafodotin) is required.

Exclusion criteria specific to AMG 701-P±d include:

* History of serious hypersensitivity associated with thalidomide, pomalidomide, or lenalidomide (\> grade 3).
* Multiple myeloma with IgM subtype.
* POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
* Contraindication to pomalidomide or dexamethasone.
* Glucocorticoid therapy within 14 days prior to randomization that exceeds a cumulative dose of 160 mg of dexamethasone or equivalent dose of other corticosteroids.
* Treatment with systemic immune modulators including, but not limited to, non-topical systemic corticosteroids (unless the dose is ≤ 10 mg/day prednisone or equivalent), cyclosporine, and tacrolimus within 2 weeks before study day 1 or 4 weeks before study day 1 for Phase 1 dose-confirmation.
* Female subjects of childbearing potential with a positive pregnancy test assessed within 14 days prior to first dose of study drugs and/or a positive urine pregnancy test within 24 hours prior to first dose. In addition, females of childbearing potential unwilling to undergo pregnancy testing weekly during the first 4 weeks of pomalidomide use followed by pregnancy testing every 4 weeks in females with regular menses or every 2 weeks in females with irregular menstrual cycles.
* Male subjects with a female partner of childbearing potential and female subjects of childbearing potential who are unwilling to use 2 methods of contraception (1 of which must be highly effective during the study and for an additional 75 days (females) and 135 days (males) after receiving the last dose of AMG 701, or 28 days after the last dose pomalidomide (males and females) or dexamethasone (females), whichever occurs later.
* Females who are lactating/breastfeeding or who plan to breastfeed while on study through 75 days after receiving the last dose of AMG 701, or 28 days after the last dose pomalidomide or dexamethasone, whichever occurs later.
* Females planning to become pregnant while on study through 75 days after receiving the last dose of AMG 701 or 28 days after the last dose pomalidomide or dexamethasone, whichever occurs later.
* Male subjects with a pregnant partner who are unwilling to practice abstinence or use a latex or synthetic condom (even if they have had a vasectomy with medical confirmation of surgical success) during treatment (including during dose interruptions) and for an additional 135 days after the last dose of AMG 701, or 28 days after the last dose pomalidomide, whichever occurs later.
* Males who are unwilling to abstain from sperm donation while on study through 135 days after receiving the last dose of AMG 701 or 28 days after the last dose pomalidomide, whichever occurs later.

Primary outcomes:
measure: Number of subjects with dose-limiting toxicities (DLTs)
timeFrame: 28 days
measure: Number of subjects with treatment emergent adverse events (TEAEs)
timeFrame: 60 months
measure: Number of subjects with treatment-related adverse events
timeFrame: 60 months
measure: Number of subjects with disease-related adverse events
timeFrame: 60 months
measure: Number of subjects with clinically-significant changes in vital signs
timeFrame: 48 months
measure: Number of subjects with clinically-significant changes in physical examination measurements
timeFrame: 48 months
measure: Number of subjects with clinically-significant changes in electrocardiogram (ECG) measurements
timeFrame: 48 months
measure: Number of subjects with clinically-significant changes in clinical laboratory tests
timeFrame: 48 months
Secondary outcomes:
measure: Pharmacokinetic parameter of AMG 701: Maximum concentration (Cmax)
timeFrame: 12 weeks
measure: Pharmacokinetic parameter of AMG 701: Time of maximum concentration (Tmax)
timeFrame: 12 weeks
measure: Pharmacokinetic parameter of AMG 701: Area under the concentration-time curve (AUC)
timeFrame: 12 weeks
measure: Pharmacokinetic parameter of AMG 701: Steady state concentration (Css)
timeFrame: 12 weeks
measure: Anti-tumor activity: Overall response rate
timeFrame: 48 months
measure: Anti-tumor activity: Best overall response of stringent complete response (sCR)
timeFrame: 48 months
measure: Anti-tumor activity: Best overall response of complete response (CR)
timeFrame: 48 months
measure: Anti-tumor activity: Best overall response of very good partial response (VGPR)
timeFrame: 48 months
measure: Anti-tumor activity: Best overall response of partial response (PR)
timeFrame: 48 months
measure: Anti-tumor activity: Duration of response
timeFrame: 48 months
measure: Anti-tumor activity: Time to response
timeFrame: 48 months
measure: Anti-tumor activity: Progression-free survival
timeFrame: 48 months
measure: Anti-tumor activity: Overall survival
timeFrame: 60 months
measure: Anti-tumor activity: Number of subjects with minimum residual disease negative complete response
timeFrame: 48 months
measure: Pharmacokinetic parameter of AMG 701: Trough concentration (Ctrough)
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic - Arizona
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences Myeloma Institute Slot 816
state: Arkansas
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute Emory U
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center - Multiple Myeloma Research Consortium
state: Illinois
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Hackensack
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New Jersey
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital, Weill Cornell Medical College
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Huntsman Cancer Institute
state: Utah
city: Milwaukee
country: United States
facility: The Medical College of Wisconsin
state: Wisconsin
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Toronto
country: Canada
facility: University Health Network-Princess Margaret Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre Glen Site
state: Quebec
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig Holstein Campus Kiel
city: Wuerzburg
country: Germany
facility: Universitaetsklinikum Wuerzburg
city: Nagoya-shi
country: Japan
facility: Nagoya City University Hospital
state: Aichi
city: Maebashi-shi
country: Japan
facility: Gunma University Hospital
state: Gunma
city: Kobe-shi
country: Japan
facility: Kobe City Medical Center General Hospital
state: Hyogo
city: Kanazawa-shi
country: Japan
facility: Kanazawa University Hospital
state: Ishikawa
city: Okayama-shi
country: Japan
facility: National Hospital Organization Okayama Medical Center
state: Okayama
city: Koto-ku
country: Japan
facility: The Cancer Institute Hospital of Japanese Foundation for Cancer Research
state: Tokyo
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Maastricht
country: Netherlands
facility: Maastricht Universitair Medisch Centrum
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Cho SF, Lin L, Xing L, Li Y, Wen K, Yu T, Hsieh PA, Munshi N, Wahl J, Matthes K, Friedrich M, Arvedson T, Anderson KC, Tai YT. The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models. Blood Adv. 2020 Sep 8;4(17):4195-4207. doi: 10.1182/bloodadvances.2020002524.