Trial Information

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

Disease background:

MM is a plasma cell tumor. It accounted for an estimated 20,180 new cases of cancer and
11,170 deaths in the United States in 2010. With a prevalence of 23 per 100,000 people, MM
is an orphan disease (prevalence <5:10,000). The median age at diagnosis is 60-65 years.
Although MM remains incurable, unprecedented gains in survival outcomes have been achieved
in the last three decades. Survival has been improved mainly in younger patients below the
age of 65 with the advent of high-dose melphalan therapy followed by autologous stem cell
transplantation (ASCT). In the last 10 years the introduction of novel therapies, such as
thalidomide, lenalidomide and bortezomib have further improved overall survival. However,
all patients ultimately relapse and will require salvage therapies.

Therapy background:

The main decision criterion for first-line treatment selection is the patient's eligibility
for high-dose chemotherapy with melphalan and subsequent ASCT. Patients who are not eligible
for this treatment, due to advanced age, comorbidities or poor performance status, are
routinely treated with a combination of melphalan, prednisone and a novel agent such as
thalidomide, bortezomib or lenalidomide. Currently, patients will relapse from their first
line of therapy at a median of 2-3 years from diagnosis. Achieving a near complete remission
and maintaining the residual tumor mass under control is considered as the mainstay in
current treatment of MM.

Treatment of relapsed/refractory myeloma is based on double or triple combinations with a
novel agent such as lenalidomide or bortezomib with dexamethasone and/or cytotoxic drugs
such as alkylators and anthracyclines. The choice of a regimen at relapse depends on the
frontline therapy as well as disease- or therapy-related comorbidities. Although patients
can achieve long lasting remissions with the novel agents MM remains a chronic disease.
Patients will invariably relapse or become refractory to second and later line treatments.
Therefore new treatment options for late-line patients are required.

The combination of lenalidomide and bortezomib has been reported to show activity in a
subset of lenalidomide and bortezomib double-refractory patients in a phase I/II trial and
very recent retrospective data suggest that bortezomib containing regimens may be active in
lenalidomide-refractory myeloma patients. There are no approved treatment options for
lenalidomide and bortezomib double-refractory patients. Possible therapeutic alternatives
such as carfilzomib and pomalidomide are still in clinical development and to date no
clinical trials are open in Switzerland. Therefore, treatment options for
lenalidomide-refractory patients remain very limited.

Preclinical results in the NCI60 cancer cell line panel show that HIV protease inhibitors
such as nelfinavir exhibit a wide spectrum of antitumor activity. They inhibit the
proliferation of 60 cancer cell lines derived from nine different tumor types. This is
consistent with previous reports demonstrating that HIV protease inhibitors are effective in
other diseases like MM and Kaposi sarcoma. Nelfinavir induces cell cycle arrest and
apoptosis in tumor cells through inhibition of proteasomal degradation and the PI3K/Akt
pathway. Therefore preclinical evidence underscores the proteasome inhibiting activity of
nelfinavir. Modulation of proteasome function is a rational approach to overcome
chemo-resistance and achieve chemo-sensitization, suggesting that the addition of such an
agent to myeloma standard treatment could restore sensitivity to the standard therapy.

Pharmacologic intervention with the PI3K/Akt pathway induced cell death in MM cell lines and
primary tumor samples. Inhibition of Akt phosphorylation by perifosine has shown significant
clinical activity and manageable toxicity in patients with relapsed/refractory MM in
combination with dexamethasone alone (≥MR (minor response) of 38%; SD (stable disease) of
47%), or together with both lenalidomide and dexamethasone (≥PR (partial response) of 50%,
MR of 20%). These data suggest an important role of the Akt pathway for malignant growth and
survival of MM cells also in vivo. The addition of nelfinavir to standard
lenalidomide/dexamethasone treatment in lenalidomide-refractory patients is expected to
restore sensitivity of the myeloma cells to lenalidomide, acting via inhibition of the
PI3K/Akt pathway and modulation of proteasome function.

Aim of this study is to demonstrate the safety and activity of combining lenalidomide and
dexamethasone with nelfinavir in patients with progressive MM that have failed
lenalidomide-containing therapy.

Treatment Nelfinavir:

Nelfinavir mesylate (Viracept) is an inhibitor of the HIV protease 1. Inhibition of this
viral protease prevents cleavage of the Gag and Gag-Pol polyproteins resulting in the
production of immature, non-infectious virus. The pharmacokinetic properties of nelfinavir
were evaluated in healthy volunteers and HIV-infected patients. No substantial differences
were observed between the two groups. In Switzerland the registered dose of nelfinavir for
the treatment of HIV-1 infection in combination with other antiretroviral agents is 1250 mg
bid or 750 mg three times daily (tid).

Plasma concentrations from a pharmacokinetic study with 10 HIV-positive patients after
multiple dosing with 1250 mg twice daily for 28 days were 4.0 mg/L (peak plasma level) and
2.2 mg/L / 0.7 mg/L (morning/evening trough), respectively. Peak plasma concentrations were
approximately 6 microM. Nelfinavir in serum is extensively protein-bound (>98%). The area
under the curve (AUC) is 1.5 times higher with the bid regimen compared to the tid regimen,
without significantly elevated toxicity. The maximal concentration of nelfinavir is usually
achieved 3 to 4 hours after administration with food. The effective half-life in blood
plasma ranges from 3 to 5 hours. Multi-dose pharmacokinetics of nelfinavir, have not been
studied in HIV-positive patients with hepatic or renal insufficiency.

Nelfinavir is an inhibitor of cytochrome P450 3A4 (CYP3A4) and is mainly metabolized by
CYP3A4 and CYP2C19. The main metabolite of nelfinavir (the hydroxylated metabolite
nelfinavir M8) is also active against HIV and circulates in the plasma at around 30% of the
present nelfinavir amount.

The dose limiting toxicity (DLT) has not been defined yet. A respective dose finding trial
for nelfinavir mono-therapy in patients with solid tumors is ongoing. Preliminary data from
that trial shows that nelfinavir is well tolerated at 2.5 times (2 x 3125 mg/day) the
American Food and Drug Administration approved dose for the treatment of HIV infections of 2
x 1250 mg/day with no grade 4-5 clinical toxicities. The most prevalent laboratory
abnormalities grade 4 with a dose level (DL) of 3125 mg bid were transaminitis,
hyperglycemia and diarrhea. The AUC of nelfinavir in plasma showed a plateau at doses of
1875 mg bid.

A phase I study of Nelfinavir in liposarcoma with a maximum DL of 4250 mg bid shows a peak
plasma level of 6.3 mg/L. One patient experienced transient grade 3 pancreatitis after one
week of nelfinavir. No other DLTs were observed.

Recent testing of this nelfinavir dose in combination with radiation therapy and weekly
gemcitabine (200-300 mg/m2) in patients with pancreatic cancer did not cause increased
toxicity in this trial.

The main side effects of nelfinavir include diarrhea (>10%), rash, elevated liver enzymes,
and reduced blood counts (1-10%) at the therapeutic standard concentration of 1250 mg bid.

Treatment Lenalidomide:

Lenalidomide (Revlimid) is a derivative of thalidomide. The exact mechanism of action of
these immunomodulatory drugs is not known. Apart from interfering with the immune system,
they are also thought to act on angiogenesis. There are multiple mechanisms of action, and
they can be simplified by organizing them as mechanisms of action in vitro and in vivo. In
vitro, lenalidomide has three main activities: direct anti-tumor effect, inhibition of the
micro-environmental support for tumor cells, and an immunomodulatory role. In vivo,
lenalidomide induces tumor cell apoptosis directly and indirectly by inhibition of bone
marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and by
immunomodulatory activity. Lenalidomide has a broad range of activities that can be
exploited to treat many hematologic and solid cancers.

Lenalidomide is one of the novel drug agents used to treat MM. It is a small molecular
analogue of thalidomide that was originally found based on its ability to effectively
inhibit tumor necrosis factor alpha (TNF-α) production. Lenalidomide is 50,000 times more
potent than thalidomide in inhibiting TNF-α, and has less severe adverse drug reactions.

The most important side effects of lenalidomide are thromboembolism and hematological
toxicity. The most common side effects are neutropenia, thrombopenia, anemia, fatigue,
constipation, diarrhea, asthenia and rash. In contrast to thalidomide, lenalidomide does not
cause neuropathies. Hematotoxicity is dose dependent and easily manageable with dose
reductions.

Lenalidomide in combination with dexamethasone is a Swissmedic approved treatment for MM
patients who have received at least one prior medicinal therapy. The combination of
lenalidomide and dexamethasone compared to dexamethasone alone led to significantly improved
progression free survival (median 11.1 vs. 4.6 months) and overall survival (median 38.0 vs.
31.6 months) in patients with relapsed or refractory myeloma in two international phase III
trials. More than 1/3 of these patients had previously been treated with the structurally
related thalidomide.

Treatment Dexamethasone:

Dexamethasone is a glucocorticosteroid that is used in the treatment of MM, which reduces
the activity of the immune system by attaching to receptors in various types of immune
cells. In MM, high-dose dexamethasone is used together with chemotherapy to make
chemotherapy more effective and to reduce certain side effects of cancer treatment, such as
nausea and vomiting.

It appears to cause apoptosis. This means that steroids such as dexamethasone can trigger
the destruction of myeloma cells. Typically dexamethasone is given with other agents - such
as vincristine, doxorubicin, thalidomide or lenalidomide - to treat MM. It has been found
that steroids can increase the ability of chemotherapeutic and immunomodulatory agents such
as lenalidomide to destroy myeloma cells.