Nelfinavir and Lenalidomide/Dexamethasone in Progressive Multiple Myeloma

• Status: Active, not recruiting
• Trial end date: 2021-12-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Swiss Group for Clinical Cancer Research
• Treatments: BB 1101; Dexamethasone; Dexamethasone 21-phosphate; Dexamethasone acetate; Lenalidomide; Nelfinavir; Thalidomide

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.