Gamma-Secretase Inhibitor RO4929097 and Cediranib Maleate in Treating Patients With Advanced Solid Tumors

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01131234
First received: May 25, 2010
Last updated: January 15, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention Phase
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
Drug: cediranib maleate
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Other: diagnostic laboratory biomarker analysis
Other: pharmacological study
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1, Pharmacokinetic and Pharmacodynamic Study of the Combination of RO4929097 and Cediranib in Patients With Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Recommended phase II dose and safety profile of gamma-secretase inhibitor RO4929097 [ Time Frame: Up to 4 weeks post-treatment ] [ Designated as safety issue: Yes ]
    Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest.


Secondary Outcome Measures:
  • Pharmacokinetic profiles for both drugs [ Time Frame: On days 1, 10, 22, and 38 of course 1, and then on day 1 of courses 2-6 ] [ Designated as safety issue: No ]
  • Pharmacodynamic effects of both drugs [ Time Frame: On days 1 and 22 of course 1 and on day 1 of course 2 ] [ Designated as safety issue: No ]
  • Preliminary antitumor efficacy [ Time Frame: Up to 4 weeks post-treatment ] [ Designated as safety issue: No ]
    Summary statistics, such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Objective response to treatment will be assessed using the RECIST criteria 1.1.


Estimated Enrollment: 50
Study Start Date: May 2010
Estimated Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (cediranib maleate and RO4929097)

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.

Drug: cediranib maleate
Given orally
Other Names:
  • AZD2171
  • Recentin
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Given orally
Other Names:
  • R4733
  • RO4929097
Other: diagnostic laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

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 in patients with advanced malignancies.

SECONDARY OBJECTIVES:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 study

    • 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 treatment
  • 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 following:

    • 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 requirements
  • 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 days
    • Cerebrovascular accident within the past 6 months
    • Symptomatic cardiac dysfunction within the past 12 months including any of the following:

      • 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 treatment
  • 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 (Coumadin®)

    • 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01131234

Locations
Canada, Ontario
Juravinski Cancer Centre at Hamilton Health Sciences
Hamilton, Ontario, Canada, L8V 5C2
Ontario Cancer Institute at Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
University Health Network-Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
Investigators
Principal Investigator: Sebastien Hotte University Health Network-Princess Margaret Hospital
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01131234     History of Changes
Other Study ID Numbers: NCI-2011-01428, NCI-2011-01428, CDR0000673867, PJC-004, 8503, U01CA132123
Study First Received: May 25, 2010
Last Updated: January 15, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
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
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases

ClinicalTrials.gov processed this record on April 23, 2014