Gamma-secretase/Notch Signalling Pathway Inhibitor RO4929097 in Combination With Cisplatin, Vinblastine, and Temozolomide in Treating Patients With Recurrent or Metastatic Melanoma

PRIMARY OBJECTIVES:

I. To characterize the safety and tolerability of daily RO4929097 (gamma-secretase/Notch
signalling pathway inhibitor RO4929097) administered orally daily in combination with CVT
(starting dose: cisplatin 25 mg/m^2 intravenous [IV] daily x 3; vinblastine 1.2 mg/m^2 IV
daily x 3, and temozolomide [TMZ] 150 mg/m^2 orally [PO] daily x 5) administered on an every
21 day schedule. (Phase Ib) II. To determine the maximum-tolerated dose (MTD) of RO4929097
with CVT in patients with metastatic melanoma with correlative biomarkers for Notch pathway
signaling and gamma secretase enzyme activity. (Phase Ib) III. Based on the MTD from the
phase Ib study, to conduct a phase II trial and to determine the response rate and overall
survival. (Phase II)

SECONDARY OBJECTIVES:

I. To describe the pharmacokinetics and pharmacodynamics of the combination of RO4929097 and
temozolomide. (Phase Ib) II. To obtain tissue biopsy for correlative studies before the
initiation of therapy and one week after treatment with RO4929097 and CVT. (Phase Ib and II)
III. To determine the progression-free survival of patients treated at the phase II dose.
(Phase II)

OUTLINE: This is phase I dose-escalation study of gamma-secretase inhibitor RO4929097,
followed by a phase II study.

Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily
(QD) on days 1-21, cisplatin IV over 30 minutes and vinblastine IV over 30 minutes on days
1-3, and temozolomide PO QD on days 1-5. Treatment repeats every 21 days for 6 courses in the
absence of disease progression or unacceptable toxicity. Patients without progressive disease
continue to receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 and
temozolomide as above in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up for 24 months.

Inclusion Criteria:

- Patients must have histologically or cytologically Memorial Sloan Kettering Cancer
Center (MSKCC) confirmed recurrent or metastatic melanoma

- All Patients must have measurable disease as defined by Response Evaluation Criteria
in Solid Tumors (RECIST) 1.1; measurable disease is defined as at least one lesion
that can be accurately measured in at least one dimension (longest diameter to be
recorded); each lesion must be > 10 mm when measured by computed tomography (CT),
magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or > 20 mm
when measured by chest x-ray; lymph nodes must be > 15 mm in short axis when measured
by CT or MRI

- Patients may have had up to one prior systemic therapy for recurrent or metastatic
disease, but cannot have previously been treated with cisplatin, vinblastine,
temozolomide, dacarbazine, or a gamma-secretase inhibitor; at least 3 weeks must have
elapsed since the last dose of systemic therapy; for small molecule targeted therapy,
at least 5 half-lives must have elapsed; at least 6 weeks must have elapsed if the
last regimen included carmustine (BCNU) or mitomycin C or an anti-cytotoxic
T-lymphocyte antigen 4 (CTLA4) antibody

- Life expectancy of greater than 3 months

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Hemoglobin >= 9 g/dL

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin =< institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 X institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Women of childbearing potential and men must use two forms of contraception (i.e.,
barrier contraception and one other method of contraception) at least 4 weeks prior to
study entry, for the duration of study participation, and for at least 12 months
post-treatment; should a woman become pregnant or suspect she is pregnant while she or
her partner are participating in this study and for 12 months after study
participation, the patient should inform the treating physician immediately

- Women of childbearing potential are required to have a negative serum pregnancy test
(with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours prior
to the first dose of RO4929097 (serum or urine); a pregnancy test (serum or urine)
will be administered every 4 weeks if their menstrual cycles are regular or every 2
weeks if their cycles are irregular while on study within the 24-hour period prior to
the administration of RO4929097; a positive urine test must be confirmed by a serum
pregnancy test; prior to dispensing RO4929097, the investigator must confirm and
document the patient's use of two contraceptive methods, dates of negative pregnancy
test, and confirm the patient's understanding of the teratogenic potential of
RO4929097

- Female patients of childbearing potential are defined as follows:

- Patients with regular menses

- Patients, after menarche with amenorrhea, irregular cycles, or using a
contraceptive method that precludes withdrawal bleeding

- Women who have had tubal ligation

- Female patients may be considered to NOT be of childbearing potential for the
following reasons:

- The patient has undergone total abdominal hysterectomy with bilateral
salpingo-oophorectomy or bilateral oophorectomy

- The patient is medically confirmed to be menopausal (no menstrual period) for 24
consecutive month

- Pre-pubertal females; the parent or guardian of young female patients who have
not yet started menstruation should verify that menstruation has not begun; if a
young female patient reaches menarche during the study, then she is to be
considered as a woman of childbearing potential from that time forward

- Ability to understand and the willingness to sign a written informed consent document

- Patients with accessible tumor must agree to undergo pre- and post-treatment tumor
biopsies

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 3 weeks earlier

- Patients may not be receiving any other investigational agents

- Patients with known brain metastases are excluded unless brain metastases have been
resected or successfully treated with stereotactic radiosurgery and the patient has
been free from central nervous system (CNS) recurrence or progression for 3 months

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to RO4929097 or other agents used in the study

- Patients taking medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible

- Preclinical studies indicate that RO4929097 is a substrate of CYP3A4 and inducer of
CYP3A4 enzyme activity; caution should be exercised when dosing RO4929097 concurrently
with CYP3A4 substrates, inducers, and/or inhibitors; furthermore, patients who are
taking concurrent medications that are strong inducers/inhibitors or substrates of
CYP3A4 should be switched to alternative medications to minimize any potential risk;
the following medications with strong potential for interaction are not allowed:
indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole,
nefazodone

- Patients with malabsorption syndrome or other condition that would interfere with
intestinal absorption

- Patients must be able to swallow tablets

- Patients who are serologically positive for hepatitis A, B or C, and have an active
infection, or have a history of liver disease, other forms of hepatitis or cirrhosis
are ineligible

- Patients with uncontrolled electrolyte abnormalities including hypocalcemia,
hypomagnesemia, hyponatremia, hypophosphatemia or hypokalemia, defined as less than
the lower limit of normal for the institution, despite adequate electrolyte
supplementation are excluded from this study

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, a history
of torsades de pointes or other significant cardiac arrhythmias other than chronic,
stable atrial fibrillation that require antiarrhythmics or other medications known to
prolong corrected QT interval (QTc); psychiatric illness/social situations that would
limit compliance with study requirements; patients may have had another cancer but
there must be convincing clinical evidence that the melanoma is the disease requiring
therapeutic intervention

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with RO4929097; these potential risks may also apply to other
agents used in this study

- HIV-positive patients on combination antiretroviral therapy are ineligible;
appropriate studies will be undertaken in patients receiving combination
antiretroviral therapy when indicated

- Cardiovascular: baseline QTc > 450 msec (male) or QTc > 470 msec (female)

- Patients who have not recovered to < Common Terminology Criteria for Adverse Events
(CTCAE) grade 2 toxicities related to prior therapy are not eligible to participate in
this study