A Study of Carfilzomib, Lenalidomide, Vorinostat, and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma (QUAD)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Hackensack University Medical Center
Sponsor:
Information provided by (Responsible Party):
Hackensack University Medical Center
ClinicalTrials.gov Identifier:
NCT01297764
First received: February 11, 2011
Last updated: August 28, 2014
Last verified: August 2014
  Purpose

This study will evaluate the feasibility of combining four of the most active agents available for the treatment of multiple myeloma. Further the investigators will attempt to assess the activity of this combination.


Condition Intervention Phase
Multiple Myeloma
Drug: Vorinostat, Lenalidomide, Carfilzomib, Dexamethasone
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Carfilzomib, Lenalidomide, Vorinostat, and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Hackensack University Medical Center:

Primary Outcome Measures:
  • Safety and dose of carfilzomib, lenalidomide, vorinostat and dexamethasone for MM [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

    Primary Objective: To evaluate safety and establish the maximum tolerated dose (MTD) [and/or a protocol defined dose below the MTD] of carfilzomib, lenalidomide, vorinostat and dexamethasone in relapsed and/or refractory multiple myeloma subjects.

    Secondary Objectives: To observe evidence of efficacy (response rate, duration of response, time to progression, time to next treatment)



Secondary Outcome Measures:
  • Overall response rate (ORR) Time to next treatment (TTNT) Time to progression (TTP) Duration of response (DOR [ Time Frame: 12 Months ] [ Designated as safety issue: Yes ]
    Secondary Objectives: To observe evidence of efficacy (response rate, duration of response, time to progression, time to next treatment)


Estimated Enrollment: 50
Study Start Date: April 2011
Estimated Study Completion Date: August 2015
Estimated Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: carfilzomib for MML
Vorinostat, Lenalidomide, Carfilzomib, Dexamethasone - This study will be conducted as an open-label Phase I/II, single-center study in which subjects will receive carfilzomib, lenalidomide, vorinostat and dexamethasone, for relapsed and/or refractory multiple myeloma. Study treatment will be administered in sequential cohorts, with 3-6 subjects in each cohort. Treatment will be administered in 28-day cycles, with the fourth week as a rest week, for 12 cycles or until disease progression or unacceptable toxicity develops.
Drug: Vorinostat, Lenalidomide, Carfilzomib, Dexamethasone

Dose Escalation Schema Cohort Carfilzomib (mg/m2) Lenalidomide (mg) Vorinostat (mg) Dexamethasone (mg)

  1. 15 15 300 40
  2. 20 15 300 40
  3. 20 25 300 40
  4. 20/27* 25 300 40
  5. 20/27* 25 400 40
Other Names:
  • Vorinostat (Zolinza)
  • Lenalidomide (Revlimid)
  • Carfilzomib (Kyprolis)
  • Dexamethasone (Decadron, Baycadron)

Detailed Description:

Phase I/II studies of the novel proteasome inhibitor, carfilzomib, have shown it to have significant activity in patients with advanced multiple myeloma, including patients with bortezomib refractory disease. This drug, unlike bortezomib, has minimal neurotoxicity and appears to have minimal gastrointestinal (GI) toxicity. Experience with the combination of bortezomib, lenalidomide and dexamethasone has shown both neuropathy and chronic diarrhea to be limiting.

Vorinostat is a histone deacetylase inhibitor with modest single agent activity in multiple myeloma. Dysesthesia, GI issues and fatigue have been problematic in this patient population. More recent studies combining vorinostat with lenalidomide and dexamethasone or with bortezomib have demonstrated a much more robust activity, including in patients refractory to lenalidomide or bortezomib-based combinations. Again, neuropathy, fatigue and GI issues have been problematic.

The investigators own anecdotal experience with combinations of proteasome inhibitor, histone deacetylase inhibitor, immunomodulators and dexamethasone has shown this combination to be extremely active and well tolerated. The combination of vorinostat, carfilzomib, lenalidomide and dexamethasone should offer the opportunity to maximize activity while limiting toxicities, particularly neuropathy and GI.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects must meet all of the following inclusion criteria to be eligible to enroll in this study:

Disease related:

  1. Symptomatic multiple myeloma
  2. Relapsed and/or refractory multiple myeloma after at least one prior therapeutic regimen for multiple myeloma
  3. Prior treatment with immunomodulatory agents, proteasome inhibitors and histone deacetylase inhibitors is permitted. (Patients who have used HDAC inhibitors, including valproic acid , must have at least 5 half-lives wash out period before beginning therapy with vorinostat on this protocol.)
  4. Measurable disease, as indicated by one or more of the following:

    • Serum M-protein ≥ 0.5 g/dL
    • Urine Bence-Jones protein ≥ 200 mg/24 h
    • If Serum Protein Electrophoresis is felt to be unreliable for routine M-protein measurement (particularly for patients with IgA MM), then quantitative immunoglobulin levels can be accepted.
    • Serum free light chain ≥ 10 mg/dL (≥ 100 mg/L) and an abnormal free light chain ratio

    Demographic

  5. Males and females ≥ 18 years of age
  6. Life expectancy of more than three months
  7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 (see Appendix B)

Laboratory

8.Adequate hepatic function, with bilirubin < 2 times the upper limit of normal (ULN) and alanine aminotransferase (ALT) < 3 times ULN 9.Absolute neutrophil count (ANC) ≥ 1,000/mm3 Hemoglobin ≥ 8 gm/dL Platelet count ≥ 50,000/ mm3 (≥ 30 × 109/L if myeloma involvement in the bone marrow is > 50%)

  • Screening ANC should be independent of granulocyte- and granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G CSF for at least 2 weeks.
  • Subjects may receive red blood cell (RBC) or platelet transfusions, if clinically indicated, in accordance with institutional guidelines
  • Screening platelet count should be independent of platelet transfusions for at least 2 weeks 10.Calculated or measured creatinine clearance of ≥60 mL/minute, calculated using the formula of Cockcroft and Gault [(140 - Age) x Mass (kg) / (72 x creatinine mg/dL)]; multiply result by 0.85 (if female). Other generally accepted calculation methods can be substituted.11.Potassium level 3.5-5.2 meq/L (institutional normal range) Ethical/Other 12.Written informed consent in accordance with federal, local, and institutional guidelines 13.Females of Child Bearing Potential* (FCBP) must have a negative serum or urine pregnancy test, with a sensitivity of at least 50 mIU/mL within 10-14 days and again within 24 hours prior to prescribing lenalidomide for cycle 1 (prescription must be filled with 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO methods of acceptable methods of birth control, one highly effective method AND one additional effective method of birth control (contraception) AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy Testing. (See Appendix G: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods)

    • A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

      14. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy (See Appendix G: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods) 15. All study participants must be registered into the mandatory RevAssist® program and be willing and able to comply with the requirements of RevAssist®.

      16. Subjects must adhere to the study visit schedule and other protocol requirements and receive outpatient treatment and laboratory monitoring at the institute that administers the drug 17. Subjects must agree to take enteric-coated aspirin 81-325 mg orally daily, or if history of prior thrombotic disease or allergy to aspirin, must be fully anticoagulated with warfarin (INR 2-3) or be treated with full-dose, low molecular weight heparin, as if to treat deep venous thrombosis (DVT)/pulmonary embolism.

Exclusion Criteria

Subjects who meet any of the following exclusion criteria are not eligible to be enrolled in this study:

Disease related

  1. Subjects with non-secretory or hyposecretory multiple myeloma, defined as <0.5 g/dL M-protein in serum and <200 mg/24 hr Bence Jones protein in urine and serum free light chain <10mg/dL (<100 mg/L) and no measurable plasmacytoma
  2. Corticosteroid therapy in a dose equivalent to dexamethasone ≥ 4 mg/day or prednisone ≥20 mg/day within 3 weeks prior to first dose
  3. Concurrent use of histone deacetylase inhibitor (eg. Valproic acid)
  4. Use of any other experimental drug or therapy within 28 days of baseline
  5. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  6. Waldenström's macroglobulinemia
  7. Chemotherapy with approved or investigative anticancer therapeutics, including steroid therapy dose as defined above, within 2 weeks prior to first dose
  8. Radiation therapy within 1 week prior to first dose, Immunotherapy within 3 weeks prior to first dose . Planned radiation therapy that occurs after the start of treatment
  9. Participation in an investigational therapeutic study within 3 weeks or within 5 drug half-lives (t1/2) prior to first dose, whichever time is greater.

    Concurrent conditions

  10. Pregnant or lactating females (Lactating females must agree not to breast feed while taking lenalidomide or vorinostat).
  11. History of allergy to boron or mannitol
  12. Major surgery within 2 weeks prior to first dose
  13. Congestive heart failure (New York Heart Association class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction in the previous six months
  14. Uncontrolled hypertension
  15. Acute active infection requiring intravenous antibiotics, antivirals, or antifungals within one week prior to first dose or oral antibiotics within 1 week
  16. Known or suspected HIV infection, known HIV seropositivity, or active hepatitis A, B, or C infection.
  17. Serious psychiatric or medical conditions that could interfere with treatment
  18. Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the first dose and/or within 14 days before enrollment
  19. Contraindication to any of the required concomitant drugs, including proton-pump inhibitor (e.g., lansoprazole), antiviral agents, enteric-coated aspirin or other anticoagulant, or if a history of prior thrombotic disease, warfarin or low molecular weight heparin
  20. Subjects in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal impairment
  21. Subjects with pleural effusions requiring therapeutic thoracentesis or ascites requiring therapeutic paracentesis
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01297764

Contacts
Contact: Palka Anand, RN 201-336-3040 PAnand@humed.com
Contact: Laura J McBride, RN, BSN, OCN 201-336-8020 Lmcbride@humed.com

Locations
United States, New Jersey
Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Laura McBride, RN    201-336-8054    LMcBride@humed.com   
Contact: Palka Anand, RN    201-996-3040    PAnand@humed.com   
Sponsors and Collaborators
Hackensack University Medical Center
Investigators
Principal Investigator: David Siegel, MD, PhD Hackensack University Medical Center
  More Information

No publications provided

Responsible Party: Hackensack University Medical Center
ClinicalTrials.gov Identifier: NCT01297764     History of Changes
Other Study ID Numbers: Pro00002074 - QUAD RV-0549
Study First Received: February 11, 2011
Last Updated: August 28, 2014
Health Authority: United States: Food and Drug Administration

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
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Vorinostat
Lenalidomide
Thalidomide
BB 1101
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Gastrointestinal Agents

ClinicalTrials.gov processed this record on August 28, 2014