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

Multiple Myeloma Clinical Trial

— QUAD  

Official title:

A Phase I/II Study of Carfilzomib, Lenalidomide, Vorinostat, and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01297764
• Other study ID #: Pro00002074 - QUAD RV-0549
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: April 2011
• Est. completion date: November 2024

Study information

• Verified date: December 2023
• Source: Hackensack Meridian Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 17
• Est. completion date: November 2024
• Est. primary completion date: November 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Vorinostat, Lenalidomide, Carfilzomib, Dexamethasone
Dose Escalation Schema Cohort Carfilzomib (mg/m2) Lenalidomide (mg) Vorinostat (mg) Dexamethasone (mg) 15 15 300 40 20 15 300 40 20 25 300 40 20/27* 25 300 40 20/27* 25 400 40

Locations

Country	Name	City	State
United States	Hackensack University Medical Center	Hackensack	New Jersey

Sponsors (1)

Lead Sponsor	Collaborator
Hackensack Meridian Health

Country where clinical trial is conducted

United States, 

References & Publications (23)

Badros A, Philip S, Niesvizky R, Goloubeva O, Harris C, Zwiebel J, et al. Phase I trial of vorinostat (suberoylanilide hydroxamic acid, SAHA) plus bortezomib (Bort) in relapsed and refractory multiple myeloma (MM) patients (pts.). EHA (European Hematology Association annual Meeting Abstracts) 2008;93(s1)0642:258

Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, Gertz M, Giralt S, Jagannath S, Vesole D. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998 Sep;102(5):1115-23. doi: 10.1046/j.1365-2141.1998.00930.x. No abstract available. — View Citation

Demo SD, Buchholz TJ, Laidig GL, Parlati F, Shenk KD, Smyth MS, et al. Biochemical and cellular characterization of the novel proteasome inhibitor PR-171. Blood 2006;106:455a.

Demo SD, Kirk CJ, Aujay MA, Buchholz TJ, Dajee M, Ho MN, Jiang J, Laidig GJ, Lewis ER, Parlati F, Shenk KD, Smyth MS, Sun CM, Vallone MK, Woo TM, Molineaux CJ, Bennett MK. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007 Jul 1;67(13):6383-91. doi: 10.1158/0008-5472.CAN-06-4086. — View Citation

Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foa R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD; Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007 Nov 22;357(21):2123-32. doi: 10.1056/NEJMoa070594. Erratum In: N Engl J Med. 2009 Jul 30;361(5):544. — View Citation

Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV; International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006 Sep;20(9):1467-73. doi: 10.1038/sj.leu.2404284. Epub 2006 Jul 20. Erratum In: Leukemia. 2006 Dec;20(12):2220. Leukemia. 2007 May;21(5):1134. — View Citation

Ivancsits D, Nimmanapali R, Sun M, Shenk K, Demo S, Bennett D, et al. The proteasome inhibitor PR-171 inhibits cell growth, induces apoptosis, and overcomes de novo and acquired drug resistance in human multiple myeloma cells. Blood 2006;106:452a.

Jawed I, Lee CM, Tward JD, Macdonald OK, Martincic D, Vudarla N, Fairbanks RK, et al. Survival outcomes for multiple myeloma over three decades: a surveillance, epidemiology, and end results (SEER) analysis. J Clin Oncol. 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007:8019.

Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk KD, Sun CM, Demo SD, Bennett MK, van Leeuwen FW, Chanan-Khan AA, Orlowski RZ. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007 Nov 1;110(9):3281-90. doi: 10.1182/blood-2007-01-065888. Epub 2007 Jun 25. — View Citation

Lonial S, Waller EK, Richardson PG, Jagannath S, Orlowski RZ, Giver CR, Jaye DL, Francis D, Giusti S, Torre C, Barlogie B, Berenson JR, Singhal S, Schenkein DP, Esseltine DL, Anderson J, Xiao H, Heffner LT, Anderson KC; SUMMIT/CREST Investigators. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood. 2005 Dec 1;106(12):3777-84. doi: 10.1182/blood-2005-03-1173. Epub 2005 Aug 11. — View Citation

Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Hideshima T, Akiyama M, Chauhan D, Munshi N, Gu X, Bailey C, Joseph M, Libermann TA, Richon VM, Marks PA, Anderson KC. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci U S A. 2004 Jan 13;101(2):540-5. doi: 10.1073/pnas.2536759100. Epub 2003 Dec 26. — View Citation

Mitsiades N, Mitsiades CS, Richardson PG, McMullan C, Poulaki V, Fanourakis G, Schlossman R, Chauhan D, Munshi NC, Hideshima T, Richon VM, Marks PA, Anderson KC. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood. 2003 May 15;101(10):4055-62. doi: 10.1182/blood-2002-11-3514. Epub 2003 Jan 16. — View Citation

Pei XY, Dai Y, Grant S. Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin Cancer Res. 2004 Jun 1;10(11):3839-52. doi: 10.1158/1078-0432.CCR-03-0561. — View Citation

Prince HM, Bishton M, Harrison S. The potential of histone deacetylase inhibitors for the treatment of multiple myeloma. Leuk Lymphoma. 2008 Mar;49(3):385-7. doi: 10.1080/10428190801950058. — View Citation

Richardson P, Schlossman RL, Mitsiades CS, Munshi NC, Colson K, Doss D, et al. Phase I clinical trial of oral administration of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with relapsed/refractory multiple myeloma (MM). [Abstract]. Blood 2004;104(11):420a.

Richardson PG, Jagannath S, Avigan DE, Alsina M, Schlossman RL, Mazumder A, et al. Lenalidomide plus bortezomib (Rev-Vel) in relapsed and/or refractory multiple myeloma (MM): final results of a multicenter phase 1 trial. Blood. 2006 Nov 16;108(11):Abstract #405.

Richardson PG, Mitsiades CS, Colson K, Reilly E, McBride L, Chiao J, et al. Final results of a phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in combination with bortezomib in patients with advanced multiple myeloma [Abstract]. Blood (ASH Annual Meeting Abstracts) 2007;110(11):1179.

Ries LAG, Melbert D, Krapcho M, Mariotto A, Miller BA, Feuer EJ, et al (eds). SEER Cancer Statistics Review, 1975-2004, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2004/, based on November 2006 SEER data submission, posted to the SEER website, 2007.

Siegel D, Weber DM, Mitsiades CS, Dimopoulo MA, Harousseau JL, Rizvi S, et al. Combined Vorinostat, Lenalidomide and Dexamethasone Therapy in Patients with Relapsed or Refractory Multiple Myeloma: A Phase I Study. [Abstract] Blood (ASH Annual Meeting Abstracts) 2009;114(22)304a.

Stewart KA, O'Connor OA, Alsina M, Trudel S, Urquilla PR, Vallone MK, et al. Phase I evaluation of carfilzomib (PR-171) in hematological malignancies: responses in multiple myeloma and Waldenstrom's macroglobulinemia at well-tolerated doses. J Clin Oncol. 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 8003.

Weber D, Badros AZ, Jagannath S, Siegel D, Richon V, Rizvi S, Garcia-Vargas J, Reiser D and Anderson KC. Vorinostat Plus Bortezomib for the Treatment of Relapsed/Refractory Multiple Myeloma (MM): Early Clinical Experience. American Society of Hematology Annual Meeting Abstract Nov 2008;112:871.

Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD; Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007 Nov 22;357(21):2133-42. doi: 10.1056/NEJMoa070596. — View Citation

Weber DM, Jagannath S, Mazumder A, Sobecks R, Schiller GJ, Gavino M, et al. Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in combination with bortezomib in patients with advanced multiple myeloma [Abstract]. Blood (ASH Annual Meeting Abstracts) 2007;110(11):1172.

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and dose of carfilzomib, lenalidomide, vorinostat and dexamethasone for MM	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)	Within 30 days of the last administration of study treatment
Secondary	Overall response rate (ORR) Time to next treatment (TTNT) Time to progression (TTP) Duration of response (DOR	Secondary Objectives: To observe evidence of efficacy (response rate, duration of response, time to progression, time to next treatment)	Within 30 days of the last administration of study treatment