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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 12/03/2020.

Aggressive Smoldering Curative Approach Evaluating Novel Therapies and Transplant

Clinicaltrials.gov identifier NCT03289299

Recruitment Status Recruiting

First Posted September 20, 2017

Last update posted August 12, 2020

Study Description

Brief summary:

This study evaluates the use of carfilzomib, lenalidomide, daratumumab, and dexamethasone in subjects with high-risk smoldering multiple myeloma (SMM). Subjects will receive treatment in 3 phases - induction (6 cycles), consolidation (6 cycles), and maintenance (12 cycles). Each cycle is 28 days.

  • Condition or Disease:Smoldering Multiple Myeloma
  • Intervention/Treatment: Drug: Carfilzomib
    Drug: Lenalidomide
    Drug: Daratumumab
    Drug: Dexamethasone
  • Phase: Phase 2
Detailed Description

This study is a multi-center phase 2 study of carfilzomib, lenalidomide, daratumumab, and dexamethasone in subjects with high-risk smoldering multiple myeloma (SMM). Myeloma remains incurable with the current approaches. The typical natural history of myeloma is one of repeated relapses, accompanied by genetic evolution and development of new abnormalities, which are often responsible for drug resistance. The presence of a precursor phase of smoldering myeloma, and the ability to identify those at the highest risk of progression, sets the stage to examine the possibility that we can cure the disease through early intervention. In order to potentially achieve this, we need to develop a highly effective combination that includes the most active drugs from different classes. Carfilzomib in combination with lenalidomide and dexamethasone results in high response rates and deep responses in subjects with newly diagnosed myeloma. Daratumumab in combination with lenalidomide results in high response rates in relapsed refractory disease. All these drugs are well tolerated and subjects are able to stay on them long term as a maintenance treatment. The combination of the carfilzomib, lenalidomide, daratumumab and dexamethasone presents the potential to enhance the effectiveness of the regimens. We hypothesize that this combination will lead to deep response including a higher proportion of minimal residual disease (MRD) negative disease among those with high risk smoldering myeloma and may translate into cure or long term disease quiescence.

Study Design
  • Study Type: Interventional
  • Estimated Enrollment: 83 participants
  • Intervention Model: Single Group Assignment
  • Intervention Model Description: Subjects will receive treatment in 3 phases - induction (6 cycles), consolidation (6 cycles), and maintenance (12 cycles).
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: Aggressive Smoldering Curative Approach Evaluating Novel Therapies (ASCENT): A Phase 2 Trial of Induction, Consolidation, and Maintenance in Subjects With High Risk Smoldering Multiple Myeloma (SMM)
  • Actual Study Start Date: May 2018
  • Estimated Primary Completion Date: June 2022
  • Estimated Study Completion Date: June 2026
Arms and interventions
Arm Intervention/treatment
Experimental: Arm A
Non-high dose treatment in 3 phases Induction 6 cycles: carfilzomib, lenalidomide, daratumumab, dexamethasone Consolidation 6 cycles: carfilzomib, lenalidomide, daratumumab, dexamethasone Maintenance 12 cycles: lenalidomide, daratumumab
Drug: Carfilzomib
56 mg/m2 IV given on days 1, 8, and 15 of each cycle during induction and consolidation phases of the study.

Drug: Lenalidomide
25 mg po given on days 1-21 of each cycle during the induction and consolidation phases. 10 mg po given on days 1-21 of each cycle during the maintenance phase.

Drug: Daratumumab
16 mg/kg IV given on days 1, 8, 15, and 22 of cycles 1-2; days 1 and 15 of cycles 3-6; day 1 of cycle 7-12; Day 1 of odd cycles for cycles 13-24.

Drug: Dexamethasone
40 mg oral given on days 1, 8, 15, and 22 of cycles 1-6 20 mg oral given on days 1, 8, 15, and 22 of cycles 7-12
Outcome Measures
  • Primary Outcome Measures: 1. Stringent complete response rate [ Time Frame: During treatment ]
    A confirmed sCR on 2 consecutive evaluations at any time during the course of treatment.
  • Secondary Outcome Measures: 1. MRD negativity after each treatment phase [ Time Frame: 6 months, 12 months, and 2 years ]
    MRD negativity after induction, consolidation, and maintenance
  • 2. MRD negativity at 1 year post treatment [ Time Frame: 1 year post treatment ]
    Persistent MRD negativity rate will be evaluated at 1 year after completion of planned treatment consisting of induction, consolidation, and maintenance.
  • 3. Overall Survival [ Time Frame: up to 10 years post registration ]
    time of registration to death due to any cause
  • 4. Progression-free survival [ Time Frame: up to 10 years post registration ]
    the time from registration to the earliest date of documentation of disease progression or death due to any cause
  • 5. Adverse events [ Time Frame: 2 years ]
    all eligible subjects that have initiated treatment will be considered evaluable for assessing adverse even rates. The maximum grade for each type of adverse event will be recorded. Relationship to trial treatment will be taken into consideration.
Eligibility Criteria
  • Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No
Criteria

Inclusion Criteria:

- Age 18 years and ≤ 80 years

- High risk smoldering myeloma, which is untreated, as defined by either of the two
following criteria:

1. Presence of any two of the following: Serum M spike > 2 gm/dL OR an involved to
uninvolved free light chain (FLC) ratio > 20 OR bone marrow PC% > 20%

2. Total score of 9 or above using the following scoring system:

FLC Ratio >10-25 = 2 >25-40 = 3 > 40 = 5

Serum M Protein (g/dL) >1.5-3 = 3 >3 = 4

BMPC% >15-20 = 2 >20-30 = 3 >30-40 = 5 >40 = 6

FISH abnormality (t(4,14), t(14,16), 1q gain, or del13q = 2

- The following laboratory values obtained 14 days prior to registration.

- Calculated creatinine clearance (using Cockcroft-Gault equation below)* ≥ 30 mL/min

- Absolute neutrophil count (ANC) ≥ 1000/mm3 (without the use of growth factors)

- Platelet count ≥ 75000/mm3

- Hemoglobin ≥8.0 g/dL

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

- alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN

- left ventricular ejection fraction (LVEF) ≥ 40%

- LVEF ≥ 40%

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (Appendix
VII)

- Previously untreated.

- Provide informed written consent.

- Negative pregnancy test done ≤14 days prior to cycle 1 day 1, for women of
childbearing potential only.

- All study participants must be registered into the mandatory Revlimid Risk Evaluation
and Mitigation Strategy (REMS®) program and be willing and able to comply with the
requirements of the REMS® program.

- Females of reproductive potential must adhere to the scheduled pregnancy testing as
required in the Revlimid REMS® program.

- Willing to follow strict birth control measures as outlined in the protocol.

Female subjects: If they are of childbearing potential, agree to one of the following:

- Practice 2 effective methods of contraception, at the same time, from the time of
signing the informed consent form through 90 days after the last dose of trial drug,
AND must also adhere to the guidelines of any treatment-specific pregnancy prevention
program, if applicable, OR

- Agree to practice true abstinence when this is in line with the preferred and usual
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of
contraception.)

Male subjects: even if surgically sterilized (i.e., status post-vasectomy), must agree to
one of the following:

- Agree to practice effective barrier contraception during the entire trial treatment
period and through 90 days after the last dose of trial drug, OR

- Must also adhere to the guidelines of any treatment-specific pregnancy prevention
program, if applicable, OR

- Agree to practice true abstinence when this is in line with the preferred and usual
lifestyle of the subject. (Periodic abstinence (e.g., calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of
contraception).

- Willing to return to enrolling institution for follow-up during the Active
Treatment Phase of the trial.

- Male subjects must agree not to donate sperm for at least 90 days after the last
dose of study treatment.

- Willing to provide samples for planned research

- Life expectancy > 6 months

- Able to take aspirin (325 mg) daily as prophylactic anticoagulation. Subjects
intolerant to aspirin may use warfarin or low dose molecular weight heparin,
novel oral anticoagulants, or low dose molecular weight heparin

Exclusion Criteria:

- monoclonal gammopathy of undetermined significance (MGUS), standard risk smoldering
myeloma, active myeloma by current IMWG definition, light chain amyloidosis with organ
involvement or patients with extramedullary disease.

- Diagnosed or treated for another malignancy ≤ 2 years before trial enrollment or
previously diagnosed with another malignancy and have any evidence of residual
disease. NOTE: Subjects with nonmelanoma skin cancer or carcinoma in situ of any type
are not excluded if they have undergone complete resection.

- If any of the following exist at screening, subject will not be eligible for trial
because this trial involves an investigational agent whose genotoxic, mutagenic and
teratogenic effects on the developing fetus and newborn are unknown:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception (per protocol)

- Other co-morbidity which would interfere with subject's ability to participate in
trial, e.g. uncontrolled infection, uncompensated heart or lung disease.

- Other concurrent chemotherapy, or any ancillary therapy considered investigational.
NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and
are thus allowed while on protocol treatment.

- Peripheral neuropathy ≥ Grade 3 on clinical examination or grade 2 with pain within 30
days prior to C1D1.

- Major surgery ≤14 days prior to C1D1.

- Evidence of current uncontrolled cardiovascular conditions, including hypertension,
cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial
infarction within the past 6 months. Note: Prior to trial entry, any ECG abnormality
at screening must be documented by the investigator as not medically relevant.

- New York Heart Association (NYHA) II, III, IV heart failure

- Known human immunodeficiency virus (HIV) positive.

- Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
antigen [HBsAg]). Subjects with resolved infection (ie., subjects who are HBsAg
negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or
antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time
polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels.
Those who are PCR positive will be excluded. EXCEPTION: subjects with serologic
findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic
marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV
DNA by PCR.

- Known or suspected active hepatitis C infection.

- Any medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol.

- Prior radiation therapy for bony lesions or plasmacytomas

- Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal
antibodies or human proteins, or their excipients (refer to respective package inserts
or Investigator's Brochure), or known sensitivity to mammalian-derived products. Known
allergies, hypersensitivity, or intolerance to trial drugs.

- Inability to comply with protocol/procedures.

Contacts and Locations
Contacts

Contact: Erica L Kim, MPH 3235330312 ekim@trevieresearch.com

Contact: Robert Wittig, MBA 9176990175 rwittig@trevieresearch.com

Locations

United States, Florida
Moffitt Cancer Center
Tampa

United States, Illinois
University of Chicago Medical Center
Chicago

United States, Indiana
Indiana University Simon Cancer Center
Indianapolis

United States, Kansas
University of Kansas Cancer Center
Westwood

United States, Maryland
University of Maryland Medical Center
Baltimore

United States, Minnesota
Mayo Clinic
Rochester

United States, New York
Weill Cornell Medicine
New York

United States, North Carolina
Levine Cancer Institute
Charlotte

United States, Washington
Swedish Cancer Institute
Seattle

United States, Wisconsin
Medical College of Wisconsin
Milwaukee

Sponsors and Collaborators

International Myeloma Foundation

Amgen

Janssen Scientific Affairs, LLC

Celgene

Trevie, Inc.

Investigators

Principal Investigator: Shaji Kumar, MD Mayo Clinic

Principal Investigator: Brian Durie, MD International Myeloma Foundation

More Information
  • Responsible Party: International Myeloma Foundation
  • ClinicalTrials.gov Identifier: NCT03289299 History of Changes
  • Other Study ID Numbers: BS001, 20159417, 54767414MMY2009, RV-CL-MM-IMF-008479
  • First Posted: September 20, 2017 Key Record Dates
  • Last Update Posted: August 12, 2020
  • Last Verified: August 2020
  • Individual Participant
    Data (IPD) Sharing
    Statement:
  • Plan to Share IPD: Undecided
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Product Manufactured in and Exported from the U.S.: Yes
  • Keywords provided by International Myeloma Foundation: myeloma
    MRD
    smoldering
  • Additional relevant MeSH terms: Multiple Myeloma
    Neoplasms, Plasma Cell
    Smoldering Multiple Myeloma