SAKK 65/08: A Phase I Trial of the HIV Protease Inhibitor Nelfinavir in Combination with Bortezomib Identifies Nelfinavir As FDA Approved, Oral Drug that Inhibits the Proteasome and Induces Proteotoxic Stress in Vivo and has Potential Antimyeloma Activity.

The HIV protease inhibitor nelfinavir has anti-myeloma activity in mice; it is approved at the 1250 mg bid dose for oral treatment of HIV. We performed a phase I dose escalation trial of nelfinavir in combination with bortezomib in patients with advanced hematologic malignancies.

During cycle 1 (28 days), trial treatment consisted of 1 week nelfinavir monotherapy, followed by nelfinavir in combination with standard dose bortezomib (1.3 mg/m²i.v. day 8, 11, 15, 18), while cycles 2 and 3 (21 days each) consisted of 2 weeks nelfinavir in combination with bortezomib (day 1, 4, 8, 11). Non-progressing patients could continue therapy for up to 4 additional cycles with the same regimen as cycles 2 and 3. Nelfinavir dose was escalated in a 3+3 design over 3 dose levels (1250, 1875, 2500 mg bid).

Dose limiting toxicity (DLT), the primary endpoint, was grade 3–4 non-hematological toxicity (excluding grade 3 bilirubin/alanine aminotransferase (ALT) or hyperlipidemia reversible within 2 weeks) or severe hematologic toxicity unrelated to the underlying disease during cycle 1. Secondary endpoints included pharmacodynamic and pharmacokinetic assessments during cycle 1 at baseline, nelfinavir monotherapy and after application of nelfinavir and bortezomib in combination, as well as signals for activity.

Twelve evaluable patients were registered (median age 58 years; 8 male; performance status 0–1 in 10/12 patients); 8 had multiple myeloma, 2 leukemia (1 acute myeloid, 1 acute lymphoblastic) and 2 lymphoma (1 diffuse large B-cell lymphoma, 1 mantle-cell (MCL)). All myeloma patients failed both prior bortezomib and lenalidomide-containing therapy; 7/8 had progressed under prior bortezomib.

One patient (2500 mg bid dose) experienced a transient grade 4 elevated ALT, categorized as DLT, which resolved within 2 weeks. The patient continued the same regimen off study without recurrent hepatic toxicity. No further DLTs occurred, thus nelfinavir 2500 mg bid was established to be safe in combination with standard dose bortezomib.

One patient with highly aggressive lymphoma died from cerebral vein thrombosis; a myeloma patient experienced a non-fatal pulmonary embolism. Elevated ALT (2 patients) was the only additional non-hematological toxicity grade 3/4 observed in >1 patient. Grade 3 febrile neutropenia and grade 4 thrombocytopenia were seen in 1 and 4 patients, respectively.

Best treatment response was evaluated for 11 patients (1 not evaluable). Partial response was achieved in 3 patients (2 myeloma, 1 MCL) and stable disease for at least 2 cycles of therapy in 5 patients. Overall, 4/12 patients completed >=3 cycles of treatment.

Assessment of proteasome activity in peripheral blood mononuclear cells (PBMC) from treated patients after 1 week nelfinavir monotherapy revealed inhibition of total proteasome activity in vivo by nelfinavir compared to baseline (mean inhibition, as determined by specific, quantitative intracellular affinity labeling of active proteasome subunits: 14.9 %, 95% confidence interval (CI): 8.8–23.5%, p=<0.001), including inhibition of the bortezomib-insensitive tryptic (β2-type) proteasome activity (mean inhibition: 17.7%, 95% CI: 8.0–27.4%, p=0.008). In addition, inhibition of pAKT, induction of the unfolded protein response and accumulation of polyubiquitinated protein in vivo was observed in PBMC after nelfinavir monotherapy. Mean intracellular proteasome inhibition after combination treatment with bortezomib and nelfinavir was 26.6 % (95% CI: 11.5–42%). Maximum nelfinavir plasma levels were observed at the 1875 mg bid dose level (Cmax mean 12.10 mM, trough mean 6.97 mM), matching the nelfinavir concentrations that mediate anti-myeloma activity in vitro.

This is the first trial to report on the use of nelfinavir as an anti-neoplastic agent in patients with hematologic malignancies. It identifies nelfinavir as FDA approved, orally available drug with pan-proteasome inhibiting activity in vivo. Nelfinavir treament up to 2500 mg bid is safe as monotherapy and in combination with standard dose bortezomib. Bortezomib in combination with nelfinavir shows signals for clinical activity in individual myeloma patients that have failed bortezomib and lenalidomide-containing therapies. Nelfinavir warrants further clinical investigation in multiple myeloma, in particular in combination with proteasome inhibitors.

No relevant conflicts of interest to declare.