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A Phase 1, Pharmacokinetic and Pharmacodynamic Study of the Combination of RO4929097 and Cediranib in Patients With Advanced Solid Tumors

Phase 1
18 Years
Open (Enrolling)
Adult Anaplastic Astrocytoma, Adult Anaplastic Ependymoma, Adult Anaplastic Oligodendroglioma, Adult Brain Stem Glioma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Adult Mixed Glioma, Male Breast Cancer, Recurrent Adult Brain Tumor, Recurrent Breast Cancer, Recurrent Colon Cancer, Recurrent Melanoma, Recurrent Non-small Cell Lung Cancer, Recurrent Ovarian Epithelial Cancer, Recurrent Ovarian Germ Cell Tumor, Recurrent Pancreatic Cancer, Recurrent Rectal Cancer, Recurrent Renal Cell Cancer, Stage III Colon Cancer, Stage III Melanoma, Stage III Ovarian Epithelial Cancer, Stage III Ovarian Germ Cell Tumor, Stage III Pancreatic Cancer, Stage III Rectal Cancer, Stage III Renal Cell Cancer, Stage IIIA Breast Cancer, Stage IIIA Non-small Cell Lung Cancer, Stage IIIB Breast Cancer, Stage IIIB Non-small Cell Lung Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer, Stage IV Colon Cancer, Stage IV Melanoma, Stage IV Non-small Cell Lung Cancer, Stage IV Ovarian Epithelial Cancer, Stage IV Ovarian Germ Cell Tumor, Stage IV Pancreatic Cancer, Stage IV Rectal Cancer, Stage IV Renal Cell Cancer, Unspecified Adult Solid Tumor, Protocol Specific

Thank you

Trial Information

A Phase 1, Pharmacokinetic and Pharmacodynamic Study of the Combination of RO4929097 and Cediranib in Patients With Advanced Solid Tumors


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 in patients with advanced malignancies.


I. To obtain 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 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 oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, and
15-17 and oral cediranib maleate once daily on days 1-21 (beginning in course 2). Courses
repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Blood and tissue samples may be collected periodically for pharmacokinetic, pharmacodynamic,
and other laboratory studies.

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

Inclusion Criteria:

- Histologically and/or cytologically confirmed solid malignancy

- Metastatic or unresectable disease

- Disease for which standard curative or palliative measures do not exist or are
no longer effective

- Patients in the expansion cohort must have one of the following malignancies:

- Breast cancer

- Malignant melanoma

- Colorectal cancer

- Pancreatic cancer

- Kidney cancer

- High-grade glioma

- Non-small cell lung cancer

- Ovarian cancer

- Measurable or non-measurable disease

- Measurable disease is defined as ≥ 1 lesion that can be accurately measured in ≥
1 dimension (longest diameter to be recorded) as ≥ 20 mm with conventional
techniques or as ≥ 10 mm with spiral CT scan

- No meningeal metastases or untreated known brain metastases

- Patients with treated brain metastasis with radiological and clinical evidence
of stability and with no evidence of cavitation or hemorrhage in the brain
lesions are eligible provided that they are asymptomatic and do not require
corticosteroids (must have discontinued steroids ≥ 1 week before randomization)

- Hormone receptor status not specified

- Menopausal status not specified

- ECOG performance status 0-1 (Karnofsky 70-100%)

- Life expectancy > 12 weeks

- 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)

- INR ≤ 1.3

- Total bilirubin normal =< institutional upper limit of normal

- AST/ALT ≤ 2.5 times upper limit of normal

- Serum creatinine normal within normal institutional limits

- LVEF ≥ 50% by ECHO/MUGA

- Urine dipstick for protein < +1 OR < 1 g on 24-hour urine collection

- 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

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

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use two forms of contraception (i.e., barrier contraception and
one other method of contraception) or abstain from sexual activity for ≥ 4 weeks
before study entry, during study, and for ≥ 12 months after completion of study

- Able to swallow medication

- No condition (e.g., gastrointestinal [GI] 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 the patients' ability to swallow or absorb oral medication

- No QTc prolongation (defined as QTc interval ≥ 450 msec in males and 470 msec in
females, by Bazett correction) or other significant ECG abnormalities (e.g.,
clinically significant arrhythmias requiring medication or conduction delays such as
2nd or 3rd degree atrioventricular blocks), including the following:

- No 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

- No need of antiarrhythmics or other concomitant medications with known potential
to prolong QT interval

- None of the following:

- Resting BP consistently systolic > 150 mm Hg and/or diastolic > 100 mm Hg (in
the presence or absence of a stable dose of antihypertensive medication)

- BP must be optimally controlled and < 150/100 mm Hg for ≥ 2 weeks before
study enrollment

- Poorly controlled hypertension

- History of labile hypertension

- Poor compliance with antihypertensive medication

- No uncontrolled concurrent illness including, but not limited to, any of the

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia other than chronic, stable atrial fibrillation

- Psychiatric illness or social situations that would limit compliance with study

- None of the following conditions:

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

- Abdominal fistula, GI perforation, or intraabdominal abscess within the past 28

- Cerebrovascular accident within the past 6 months

- Symptomatic cardiac dysfunction within the past 12 months including any of the

- Unstable angina

- NYHA class III or IV congestive heart failure

- Myocardial infarction

- Cardiac angioplasty or stenting or bypass

- No serologic positivity for hepatitis A, B, or C or history of liver disease or other
forms of hepatitis or cirrhosis

- No HIV-positive patients on combination antiretroviral therapy

- No diarrhea ≥ grade 2 not under control with standard anti-diarrhea medications

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to gamma-secretase inhibitor RO4929097 and/or cediranib maleate

- Female patients may not donate ova during or after study treatment

- Male patients may not donate sperm during and for ≥ 12 months after completion of
study treatment

- Patients may not donate blood during and for ≥ 12 months after completion of study

- No concurrent treatment with known potential to prolong QT interval

- Any number of prior treatment regimens allowed

- Prior angiogenesis inhibitors (e.g., sorafenib, bevacizumab) allowed

- Prior anthracyclines allowed

- Recovered from the adverse events due to previous treatment to < CTCAE grade 2
(except alopecia)

- No prior gamma-secretase inhibitor and/or cediranib maleate

- At least 4 weeks since prior radiotherapy or systemic therapy (6 weeks for
carmustine, nitrosoureas, or mitomycin C)

- Exceptions may be made for low-dose, non-myelosuppressive radiotherapy for
systemic palliation

- More than 30 days since prior and no other concurrent investigational agents

- At least 14 days since prior and no concurrent medications with narrow therapeutic
indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium

- Low-dose warfarin for prophylaxis for central catheters is allowed

- No concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4

- No concurrent medications or food (including ketoconazole, grapefruit, or grapefruit
juice) that may interfere with the metabolism of study drugs

- No other concurrent investigational or commercial agents or therapies administered
with the intent to treat the patient's malignancy

- Patients with castration-resistant prostate cancer may continue luteinizing
hormone-releasing hormone-agonist therapy

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Recommended phase II dose and safety profile of gamma-secretase inhibitor RO4929097

Outcome Description:

Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest.

Outcome Time Frame:

Up to 4 weeks post-treatment

Safety Issue:


Principal Investigator

Sebastien Hotte

Investigator Role:

Principal Investigator

Investigator Affiliation:

University Health Network-Princess Margaret Hospital


United States: Food and Drug Administration

Study ID:




Start Date:

May 2010

Completion Date:

Related Keywords:

  • Adult Anaplastic Astrocytoma
  • Adult Anaplastic Ependymoma
  • Adult Anaplastic Oligodendroglioma
  • Adult Brain Stem Glioma
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Adult Mixed Glioma
  • Male Breast Cancer
  • Recurrent Adult Brain Tumor
  • Recurrent Breast Cancer
  • Recurrent Colon Cancer
  • Recurrent Melanoma
  • Recurrent Non-Small Cell Lung Cancer
  • Recurrent Ovarian Epithelial Cancer
  • Recurrent Ovarian Germ Cell Tumor
  • Recurrent Pancreatic Cancer
  • Recurrent Rectal Cancer
  • Recurrent Renal Cell Cancer
  • Stage III Colon Cancer
  • Stage III Melanoma
  • Stage III Ovarian Epithelial Cancer
  • Stage III Ovarian Germ Cell Tumor
  • Stage III Pancreatic Cancer
  • Stage III Rectal Cancer
  • Stage III Renal Cell Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIA Non-Small Cell Lung Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIB Non-Small Cell Lung Cancer
  • Stage IIIC Breast Cancer
  • Stage IV Breast Cancer
  • Stage IV Colon Cancer
  • Stage IV Melanoma
  • Stage IV Non-Small Cell Lung Cancer
  • Stage IV Ovarian Epithelial Cancer
  • Stage IV Ovarian Germ Cell Tumor
  • Stage IV Pancreatic Cancer
  • Stage IV Rectal Cancer
  • Stage IV Renal Cell Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Astrocytoma
  • Brain Neoplasms
  • Breast Neoplasms
  • Colonic Neoplasms
  • Rectal Neoplasms
  • Carcinoma, Non-Small-Cell Lung
  • Carcinoma, Renal Cell
  • Ependymoma
  • Glioblastoma
  • Glioma
  • Lung Neoplasms
  • Melanoma
  • Oligodendroglioma
  • Pancreatic Neoplasms
  • Neoplasms, Germ Cell and Embryonal
  • Gliosarcoma
  • Breast Neoplasms, Male
  • Germinoma
  • Ovarian Neoplasms
  • Neoplasms
  • Neoplasms, Glandular and Epithelial