Nelfinavir and Lenalidomide/Dexamethasone in Patients With Progressive Multiple Myeloma That Have Failed Lenalidomide-containing Therapy

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Swiss Group for Clinical Cancer Research
Sponsor:
Information provided by (Responsible Party):
Swiss Group for Clinical Cancer Research
ClinicalTrials.gov Identifier:
NCT01555281
First received: March 8, 2012
Last updated: February 7, 2014
Last verified: February 2014
  Purpose

There is a great need for treatment options in patients with multiple myeloma (MM) after failure of the lenalidomide/dexamethasone regimen as there is no established standard active therapy for these patients.

Combining nelfinavir, a drug targeting both the proteasome and PI3K/Akt pathway, with lenalidomide, may restore lenalidomide-sensitivity to the disease as has been shown in vivo for the PI3K/Akt inhibitor perifosine and the proteasome inhibitor bortezomib.

Patients expected to be included in the trial are heavily pretreated and might not be candidates for further intensive therapies. The combination of nelfinavir with lenalidomide/dexamethasone offers also to these patients an alternative. Preliminary experiences in another SAKK trial with the combination of bortezomib and nelfinavir are positive with few side effects with nelfinavir doses of up to 1875 mg twice daily (bid). For the phase I part of the trial a starting dose of 1250 mg nelfinavir bid was chosen, since the necessary plasma concentration of nelfinavir will not be reached with lower doses.

In case of progression during or after the trial treatment any other lenalidomide- or bortezomib-based chemotherapy combination could be an option for the patient. However, the addition of a chemotherapeutic drug like cyclophosphamide or doxorubicin has known side effects like hematological toxicities, nausea, vomiting and hair loss.

The aim of this trial is to demonstrate that the combination of nelfinavir with lenalidomide/dexamethasone is safe (phase I, dose escalation of nelfinavir) and active (phase II). Patients who do not respond to trial medication will stop trial treatment after 4 months of therapy at the latest.

If the combination of nelfinavir with lenalidomide/dexamethasone should prove to be safe and efficient in treatment of lenalidomide-refractory MM, this would be the first orally available treatment for these patients and establish a new class of drugs (human immunodeficiency virus (HIV) protease inhibitors) as active antineoplastic agents in MM. In addition this would establish the concept of "re-sensitizing" patients to lenalidomide therapy and demonstrate the effect of nelfinavir on proteasomal degradation and Akt phosphorylation in cancer patients in vivo.


Condition Intervention Phase
Multiple Myeloma
Drug: Nelfinavir
Drug: Lenalidomide
Drug: 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: Nelfinavir and Lenalidomide/Dexamethasone in Patients With Progressive Multiple Myeloma That Have Failed Lenalidomide-containing Therapy - A Single Arm Phase I/II Trial

Resource links provided by NLM:


Further study details as provided by Swiss Group for Clinical Cancer Research:

Primary Outcome Measures:
  • Phase I: Dose limiting toxicity [ Time Frame: Until up to 4 weeks after start of trial therapy ] [ Designated as safety issue: Yes ]
  • Phase II: Overall response [ Time Frame: 16 weeks after the start of trial therapy ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Phase I/II: Frequency and percent of occurrence of adverse events during each cycle of treatment, and within patients [ Time Frame: Until 30 days after up to 16 weeks of trial therapy ] [ Designated as safety issue: Yes ]
  • Phase I/II: Disease control, i.e. no progression at 16 weeks after start of trial therapy [ Time Frame: At 16 weeks after the start of trial therapy ] [ Designated as safety issue: No ]
  • Phase I/II: Duration of response [ Time Frame: Duration from first observation of response to the time of disease progression, with deaths due to causes other than progression censored, assessed until an expected maximum of 3 years ] [ Designated as safety issue: No ]
  • Phase I/II: Overall survival [ Time Frame: At 6 months after start of trial therapy ] [ Designated as safety issue: No ]
  • Phase I/II: Progression free survival [ Time Frame: Progression free survial time ] [ Designated as safety issue: No ]
  • Phase I/II: Time to progression [ Time Frame: Duration from start of treatment to disease progression, with deaths due to causes other than progression censored, assessed until an expected maximum of 3 years ] [ Designated as safety issue: No ]
  • Phase I: Overall response [ Time Frame: 16 weeks after the start of trial therapy ] [ Designated as safety issue: No ]

Estimated Enrollment: 32
Study Start Date: April 2012
Estimated Study Completion Date: December 2019
Estimated Primary Completion Date: December 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Nelfinavir and Lenalidomide/Dexamethasone

Phase I: Cycles 1-4 (1 cycle = 28 days) Lenalidomide: 25 mg per day p.o., day 1 to 21 Dexamethasone: 40/20 mg per day p.o., days 1, 8, 15, 22 Nelfinavir: Dose escalation in cohorts of 3 patients

Phase II: Cycles 1-4 (1 cycle = 28 days) Lenalidomide: 25 mg per day p.o., day 1 to 21 Dexamethasone: 40/20 mg per day p.o., days 1, 8, 15, 22 Nelfinavir: Dose established in phase I twice daily p.o., day 1 to 21

Drug: Nelfinavir
In phase II, the recommended dose of nelfinavir will be administered orally twice daily (in the morning and in the evening) on d1-d21 every 28 days for a maximum of 4 cycles
Other Name: Viracept
Drug: Lenalidomide
25 mg of lenalidomide (capsules) will be administered orally daily on d1-d21 every 28 days for a maximum of 4 cycles
Other Name: Revlimid
Drug: Dexamethasone
40 mg (for patients <75 years) or 20 mg (for patients ≥75 years) of dexamethasone (tablets) will be administered orally once per day on d1, 8, 15 and 22 every 28 days for a maximum of 4 cycles
Other Name: Dexamethasone

  Show Detailed Description

  Eligibility

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

Inclusion Criteria:

  • Patient must have given written informed consent (including the drug-specific informed consent for Revlimid) before registration.
  • Multiple myeloma having progressed after at least two months of lenalidomide-containing therapy (progressive disease during treatment with lenalidomide or <60 days after such treatment).
  • Measurable disease for myeloma defined as one of the following:

    1. Serum monoclonal protein (M-protein) ≥10 g/L IgG or ≥5 g/L IgA, IgM, IgD
    2. Urine M-protein ≥200 mg/24h
    3. To be considered only if patient has no evidence of measurable disease with one of the criteria above: serum free light chain (FLC) ratio of kappa/lambda either >1.65 or <0.26 (baseline level of involved FLC has to be ≥100 mg/L)
  • Adverse events from previous treatment has recovered to grade ≤2.
  • Age ≥18 years.
  • WHO performance status 0-2.
  • Adequate hematological values: neutrophils ≥1 x 109/L, platelets ≥75 x 109/L
  • Adequate hepatic function: bilirubin ≤1.5 x ULN, AST and AP ≤2.5 x ULN
  • Adequate renal function: calculated creatinine clearance >50 mL/min, according to the formula of Cockcroft-Gault
  • Adequate cardiac function: EF ≥40% assessed by echocardiography or MUGA scan
  • Negative HIV test.
  • Women are not breastfeeding. Women of child-bearing potential are using effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and during the 12 months thereafter. A negative serum pregnancy test (minimum sensitivity of 25 mIU/ml) before inclusion (within 7 days) into the trial is required for all women of child-bearing potential. Men agree not to father a child during participation in the trial and during 12 months thereafter.
  • Patient compliance and geographic proximity allow proper staging and follow-up.

Exclusion Criteria:

  • Previous malignancy within 2 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer.
  • Psychiatric disorder precluding understanding of information on trial related topics, giving informed consent, filling patient diary, or interfering with compliance for oral drug intake.
  • Concurrent treatment with other experimental drugs or other anti-cancer therapy (chemotherapeutical/biological agents, radiation therapy). Treatment in a clinical trial within 30 days prior to trial entry.
  • Known hypersensitivity or uncontrolled side effects related to trial drug(s) or hypersensitivity to any other component of the trial drugs.
  • Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information.
  • Any serious underlying medical condition (at the judgment of the investigator) which could impair the ability of the patient to participate in the trial (e.g. active autoimmune disease, uncontrolled diabetes).
  • Unstable cardiovascular disease.
  • Known or clinically suspected myeloma manifestations in the central nervous system.
  • Previous grade 4 adverse events attributable to treatment with lenalidomide.
  • Patients who are on strong CYP3A4 modulators that cannot be replaced at least one week before the first dose of trial drugs and for the period of the trial.
  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: NCT01555281

Contacts
Contact: Felicitas Hitz, MD +41 71 494 10 66 felicitas.hitz@kssg.ch

Locations
Italy
Istituto Europeo di Oncologia IEO Not yet recruiting
Milano, Italy, 20141
Contact: Giovanni Martinelli, Prof.    +39 (02) 57489 538    giovanni.martinelli@ieo.it   
University of Torino Not yet recruiting
Torino, Italy, 10127
Contact: Antonio Palumbo, Prof.    +39 (01) 16336 107    appalumbo@yahoo.com   
Switzerland
Kantonsspital Aarau Recruiting
Aarau, Switzerland, 5001
Contact: Mario Bargetzi, Prof.    +41 62 838 60 53    mario.bargetzi@ksa.ch   
Principal Investigator: Bargetzi Mario, Prof         
Istituto Oncologico Svizzera Italiana IOSI Recruiting
Bellinzona, Switzerland, 6500
Contact: Erika Lerch, MD    +41 91 811 91 11    erika.lerch@eoc.ch   
Principal Investigator: Erika Lerch, MD         
Inselspital Bern Recruiting
Bern, Switzerland, 3010
Contact: Thomas Pabst, Prof.    +41 31 632 84 30    thomas.pabst@insel.ch   
Principal Investigator: Thomas Pabst, Prof         
Kantonsspital Graubünden Recruiting
Chur, Switzerland, 7000
Contact: Ulrich Mey, PD    +41 81 256 71 70    ulrich.mey@ksgr.ch   
Principal Investigator: Ulrich Mey, MD         
Kantonsspital Luzern Not yet recruiting
Luzern, Switzerland, 6000
Contact: Ralph Winterhalder, MD    +41 41 205 58 75    ralph.winterhalder@ksl.ch   
Kantonsspital Olten Recruiting
Olten, Switzerland, 4600
Contact: Dorothea Friess, MD    +41 62 311 41 79    dorothea.friess@spital.so.ch   
Principal Investigator: Dorothea Friess, MD         
Kantonsspital St. Gallen Recruiting
St. Gallen, Switzerland, 9007
Contact: Felicitas Hitz, MD    +41 71 494 10 66    felicitas.hitz@kssg.ch   
Principal Investigator: Felicitas Hitz, MD         
Regionalspital Recruiting
Thun, Switzerland, 3600
Contact: Daniel Rauch, MD    +41 33 226 26 45    daniel.rauch@spitalstsag.ch   
Principal Investigator: Daniel Rauch, MD         
Universitäts Spital Zürich Recruiting
Zürich, Switzerland, 8091
Contact: Samaras Panagiotis, Dr    +41 44 255 22 14    panagiotis.samaras@usz.ch   
Principal Investigator: Panagiotis Samaras, MD         
Sponsors and Collaborators
Swiss Group for Clinical Cancer Research
Investigators
Study Chair: Felicitas Hitz, MD Kantonsspital, CH-9007 St. Gallen
  More Information

Additional Information:
No publications provided

Responsible Party: Swiss Group for Clinical Cancer Research
ClinicalTrials.gov Identifier: NCT01555281     History of Changes
Other Study ID Numbers: SAKK 39/10, 2010-022035-11
Study First Received: March 8, 2012
Last Updated: February 7, 2014
Health Authority: Switzerland: Swissmedic

Keywords provided by Swiss Group for Clinical Cancer Research:
Multiple Myeloma
Kahler Disease
Lenalidomide
Revlimid
Nelfinavir
Viracept
Dexamethasone

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
Lenalidomide
Thalidomide
BB 1101
Nelfinavir
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 July 23, 2014