Nelfinavir and Lenalidomide/Dexamethasone in Progressive Multiple Myeloma

NCT01555281 | Terminated Phase 1 DMC

• 3 other identifiers: SAKK 39/102010-022035-11000001246
• Study Type: interventional
• Target: 33
• Locations: 2 countries
• Sites: 11

Brief Summary

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.

Conditions

Multiple Myeloma

Keywords

Multiple Myeloma; Kahler Disease; Lenalidomide; Revlimid; Nelfinavir; Viracept; Dexamethasone

Outcome Measures

Primary Outcomes (2)

• Phase I: Dose limiting toxicity

  Until up to 4 weeks after start of trial therapy

• Phase II: Overall response

  16 weeks after the start of trial therapy

Secondary Outcomes (7)

• Phase I/II: Frequency and percent of occurrence of adverse events during each cycle of treatment, and within patients

  Until 30 days after up to 16 weeks of trial therapy

• Phase I/II: Disease control, i.e. no progression at 16 weeks after start of trial therapy

  At 16 weeks after the start of trial therapy

• Phase I/II: Duration of response

  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

• Phase I/II: Overall survival

  At 6 months after start of trial therapy

• Phase I/II: Progression free survival

  Progression free survial time

Study Arms (1)

Nelfinavir and Lenalidomide/Dexamethasone

EXPERIMENTAL

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; Drug: Lenalidomide; Drug: Dexamethasone

Interventions

Nelfinavir DRUG

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

Also known as: Viracept

Nelfinavir and Lenalidomide/Dexamethasone

Lenalidomide DRUG

25 mg of lenalidomide (capsules) will be administered orally daily on d1-d21 every 28 days for a maximum of 4 cycles

Also known as: Revlimid

Nelfinavir and Lenalidomide/Dexamethasone

Dexamethasone DRUG

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

Nelfinavir and Lenalidomide/Dexamethasone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Serum monoclonal protein (M-protein) ≥10 g/L IgG or ≥5 g/L IgA, IgM, IgD
• Urine M-protein ≥200 mg/24h
• 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.
• Patient compliance and geographic proximity allow proper staging and follow-up.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Swiss Cancer Institute: lead

Study Sites (11)

Istituto Europeo di Oncologia IEO

Milan, 20141, Italy

Location

University of Torino

Torino, 10127, Italy

Location

Kantonsspital Aarau

Aarau, 5001, Switzerland

Location

Kantonsspital Baden

Baden, 5404, Switzerland

Location

Istituto Oncologico Svizzera Italiana IOSI

Bellinzona, 6500, Switzerland

Location

Inselspital Bern

Bern, 3010, Switzerland

Location

Kantonsspital Graubünden

Chur, 7000, Switzerland

Location

Kantonsspital Olten

Olten, 4600, Switzerland

Location

Kantonsspital St. Gallen

Sankt Gallen, 9007, Switzerland

Location

Regionalspital

Thun, 3600, Switzerland

Location

UniversitätsSpital Zürich

Zurich, 8091, Switzerland

Location

Related Links

• SAKK - SWISS GROUP FOR CLINICAL CANCER RESEARCH

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Nelfinavir; Lenalidomide; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Isoquinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Isoindoles; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Felicitas Hitz, MD

  Kantonsspital, CH-9007 St. Gallen

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 8, 2012
• First Posted: March 15, 2012
• Study Start: February 23, 2012
• Primary Completion: June 8, 2022
• Study Completion: June 8, 2022
• Last Updated: July 7, 2022

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will not share

Locations

CH (9); IT (2)