Gamma-Secretase Inhibitor RO4929097 and Cediranib Maleate in Treating Patients With Advanced Solid Tumors
Gamma-Secretase Inhibitor RO4929097 and Cediranib Maleate in Treating Patients With Advanced Solid Tumors
This phase I clinical trial is studying the side effects and best dose of giving
 gamma-secretase inhibitor RO4929097 and cediranib maleate together in treating patients with
 advanced solid tumors. Gamma-secretase inhibitor RO4929097 and cediranib maleate may stop the
 growth of tumor cells by blocking some of the enzymes needed for cell growth. Cediranib
 maleate also may stop the growth of tumor cells by blocking blood flow to the tumor.
PRIMARY OBJECTIVES:

 I. To determine the tolerability, maximum tolerated dose (equivalent to the recommended phase
 II dose), and safety profile of RO4929097 (gamma-secretase inhibitor RO4929097) in
 combination with cediranib (cediranib maleate) in patients with advanced malignancies.

 SECONDARY OBJECTIVES:

 I. To obtain pharmacokinetic (PK) profiles for RO4929097 when administered alone and for
 RO492907 and cediranib in combination, in order to evaluate for interactive effects in PK (if
 any) between these two agents.

 II. To evaluate pharmacodynamic (PD) effects of RO492907 when administered alone and in
 combination, with the goal of identifying potential predictive and PD markers that need
 further exploration and validation in future trials.

 III. To assess for preliminary antitumor efficacy of this drug combination, especially in
 breast cancer, malignant melanoma, colorectal cancer, pancreatic cancer, kidney cancer, high
 grade glioma, non-small-cell lung cancer, and ovarian cancer.

 OUTLINE: This is a dose-escalation study.

 Patients receive gamma-secretase inhibitor RO4929097 orally (PO) once daily (QD) on days 1-3,
 8-10, and 15-17 (days 1-3, 8-10, 15-17 22-24, 29-31, and 36-38 of course 1) and cediranib
 maleate PO QD on days 1-21 (days 22-42 course 1 only). Courses repeat every 21 days in the
 absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up for 4 weeks.
Inclusion Criteria:

 -  Dose-escalation cohorts: Patients must have histologically and/or cytologically
 confirmed solid malignancy that is metastatic or unresectable and for which standard
 curative or palliative measures do not exist or are no longer effective; expansion
 cohort: patients must have histologically and/or cytologically confirmed breast
 cancer, malignant melanoma, colorectal cancer, pancreatic cancer, kidney cancer, high
 grade glioma, non-small-cell lung cancer, or ovarian cancer

 -  Patients must have measurable or non-measurable disease; measurable disease is defined
 as at least one lesion that can be accurately measured in at least one dimension
 (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10
 mm with spiral computed tomography (CT) scan; measurable disease is not required to
 participate in this trial

 -  No limitation on prior therapy; however, there must be at least a 4 week interval
 between initiation of study treatment and any prior radiotherapy or systemic therapy,
 6 weeks if the last regimen included carmustine (BCNU) or mitomycin C; exceptions may
 be made however, for low dose, non-myelosuppressive radiotherapy for symptomatic
 palliation; please contact the Princess Margaret Hospital (PMH) Phase I Consortium
 Central Office coordinator or the Principal Investigator if any questions arise about
 interpretation of this criterion

 -  Life expectancy of greater than 12 weeks

 -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

 -  Leukocytes >= 3.0 x 10^9/L

 -  Absolute neutrophil count >= 1.5 x 10^9/L

 -  Platelets >= 100 x 10^9/L

 -  Hemoglobin >= 90 g/L (or >= 9 g/dL)

 -  International normalized ratio (INR) =< 1.3

 -  Total bilirubin normal =< institutional upper limit of normal

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
 < 2.5 x institutional upper limit of normal

 -  Serum creatinine < institutional upper limit of normal OR creatinine clearance >= 60
 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

 -  Left ventricular ejection fraction (LVEF) >= 50% by echocardiogram (ECHO)/multi gated
 acquisition scan (MUGA)

 -  Urine dipstick for protein of less than +1; for +1 or greater than +1 proteinuria on 2
 consecutive dipsticks taken no longer than 1 week apart, 24-hour urine for protein is
 necessary and should be < 1 g/24 hours

 -  Patients must be able to swallow medication

 -  If women of childbearing potential do not abstain* from sexual activity they must use
 two forms of contraception (i.e., barrier contraception and one other method of
 contraception) at least 4 weeks prior to study entry; women of childbearing potential
 can either be abstinent or use two forms of contraception for the duration of study
 participation and for at least 12 months post-treatment; men must use condoms when
 sexually active with women for the duration of study participation and 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

 -  Abstinent from sexual activity at least 4 weeks prior to study entry

 -  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 3 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 and /or cediranib; a
 positive urine test must be confirmed by a serum pregnancy test; prior to
 dispensing RO4929097 and /or cediranib, the investigator must confirm and
 document the patient's use of two contraceptive methods or abstinence, dates of
 negative pregnancy test, and confirm the patient's understanding of the
 teratogenic potential of RO4929097 and cediranib

 -  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 months

 -  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

 -  Archival tissue availability with consent for pharmacodynamic analysis is highly
 preferred but NOT an inclusion criterion

 Exclusion Criteria:

 -  Patients who have had systemic therapy or radiotherapy or major surgery within 4 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 4 weeks
 earlier

 -  Patients may not be receiving any other investigational agents within the past 30 days
 or have been previously treated with a gamma-secretase inhibitor and/or cediranib;
 exposure to other angiogenesis inhibitors (e.g. sorafenib, bevacizumab) is acceptable

 -  Patients with any meningeal metastases or untreated known brain metastases should be
 excluded from this clinical trial; patients with treated brain metastasis with
 radiologic and clinical evidence of stability, with no evidence of cavitation or
 hemorrhage in the brain lesions, are eligible providing that they are asymptomatic and
 do not require corticosteroids (must have discontinued steroids at least 1 week prior
 to randomization)

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to RO4929097 and/or cediranib used in the study

 -  Patients taking medications with narrow therapeutic indices that are metabolized by
 cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible (except
 low dose warfarin for prophylaxis for central catheters)

 -  Patients who are taking concurrent medications that are strong inducers/inhibitors or
 substrates of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) should be
 switched to alternative medications to minimize any potential risk; if such patients
 cannot be switched to alternative medications, they will be ineligible to participate
 in this study

 -  Patients with any condition (e.g., gastrointestinal tract disease resulting in an
 inability to take oral medication or a requirement for IV alimentation, active peptic
 ulcer disease, short gut syndrome, malabsorption syndrome of any type, total or
 partial bowel obstruction or inability to tolerate oral medications) that potentially
 impairs their ability to swallow or absorb are excluded

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

 -  Patients with uncontrolled 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

 -  Note: it is acceptable to use corrected calcium when interpreting calcium levels

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
 arrhythmia other than chronic, stable atrial fibrillation, or psychiatric
 illness/social situations that would limit compliance with study requirements

 -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
 the mother is treated with RO4929097 with or without cediranib

 -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
 therapy are ineligible

 -  Patients with corrected QT interval (QTc) prolongation (defined as QTc interval >= 450
 msec in males and 470 msec in females, by Bazett correction) or other significant
 electrocardiogram (ECG) abnormalities (i.e. clinically significant arrhythmias
 requiring medication or conduction delays such as 2nd or 3rd degree atrioventricular
 blocks, etc) are ineligible

 -  History of risk factors for QT interval prolongation, including, but not limited
 to family or personal history of long QT syndrome, history of torsades de
 pointes, recurrent syncope without known etiology or sudden unexpected death

 -  The need for antiarrhythmics or other concomitant medications with known
 potential to prolong QT interval

 -  Patients who have not recovered from side effects of previous systemic anticancer
 therapy to < Common Terminology Criteria for Adverse Events (CTCAE) grade 2 (except
 alopecia) prior to the first dose of combination

 -  Patients with a >= grade 2 diarrhea not under control with standard anti-diarrhea
 medications

 -  Patients with resting blood pressure (BP) consistently higher than, systolic > 150
 mmHg and/or diastolic > 100 mmHg (in the presence or absence of a stable dose of
 anti-hypertensive medication) or poorly controlled hypertension, history of labile
 hypertension or poor compliance with anti-hypertensive medication

 -  Blood pressure needs to be optimally controlled and < 150/100 for a period of at
 least 2 weeks prior to enrollment into the study

 -  Patients with any of the following conditions are excluded:

 -  Serious or non-healing wound, ulcer, or bone fracture

 -  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
 abscess within the past 28 days of treatment

 -  Any history of cerebrovascular accident (CVA) within the past 6 months

 -  Prophylactic low-dose warfarin is permitted, but close monitoring of INR must be
 performed; baseline INR must meet the inclusion criteria; note: low molecular
 weight heparin is permitted

 -  History of symptomatic cardiac dysfunction within the last 12 months including
 unstable angina, congestive heart failure (class III or IV heart failure as
 defined by the New York Heart Association [NYHA] functional classification
 system, myocardial infarction, cardiac angioplasty or stenting or bypass;
 patients with a significant cardiac history, even if controlled, should have a
 LVEF of >= 50% by ECHO or MUGA prior to study entry

 -  Patients previously treated with anthracyclines are eligible as long as their ejection
 fraction is > 50% by ECHO or MUGA prior to study entry