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About
This phase I/II clinical trial is studying the side effects and best dose of gamma-secretase inhibitor RO4929097 and to see how well it works in treating young patients with relapsed or refractory solid tumors, CNS tumors, lymphoma, or T-cell leukemia. Gamma-secretase inhibitor RO4929097 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Full description
PRIMARY OBJECTIVES:
I. To estimate the maximum-tolerated dose (MTD) and recommend a phase II dose of gamma-secretase inhibitor RO4929097 administered orally to children with relapsed or refractory solid tumors or lymphoma on two schedules: once daily orally on a 3-day on/4-day off weekly schedule (schedule A) or once daily for 5 consecutive days weekly schedule (schedule B).
II. To define and describe the toxicities of this drug administered on these schedules to children with relapsed or refractory solid tumors, lymphoma, or T-cell leukemia.
III. To estimate the MTD and recommended phase II dose of gamma-secretase inhibitor RO4929097 administered with dexamethasone.
IV. To define and describe the toxicities of gamma-secretase inhibitor RO4929097 administered with dexamethasone.
V. To characterize the pharmacokinetics of gamma-secretase inhibitor RO4929097 in children with refractory cancer.
SECONDARY OBJECTIVES:
I. To preliminarily define the antitumor activity of gamma-secretase inhibitor RO4929097 in children with solid or CNS tumors and lymphoma within the confines of a phase I study.
II. To obtain initial efficacy data on the antitumor activity of gamma-secretase inhibitor RO4929097 when combined with dexamethasone in children with relapsed-refractory T-cell leukemia (T-acute lymphoblastic leukemia [ALL]).
III. To study the effect of gamma-secretase inhibitor RO4929097 on Hes1 (hairy/enhancer of split) and other components of the Notch signaling pathway in peripheral blood mononuclear cells and/or T-ALL blasts. (exploratory) IV. To examine archival tumor samples for expression of JAGGED1, JAGGED2, cleaved NOTCH1, and HES1, and HES5 by IHC and for amplification of NOTCH1 or NOTCH2 using FISH analysis. (exploratory) V. To preliminarily assess changes following treatment with gamma-secretase inhibitor RO4929097 using FDG PET imaging. (exploratory)
OUTLINE: This is a multicenter, phase I, dose-escalation study of gamma-secretase inhibitor RO4929097 followed by a phase II study. Patients are enrolled sequentially to group A or B.
GROUP A: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, 15-17, and 22-24. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
GROUP B: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-5, 8-12, 15-19, and 22-26. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Patients may also receive concurrent oral dexamethasone twice daily on the days of gamma-secretase inhibitor RO4929097 administration.
Once the MTD or recommended phase II dose of RO4929097 plus dexamethasone in children with solid tumors, including CNS tumors, or lymphoma has been identified, this dose is used for patients with relapsed-refractory T-ALL (phase 2 portion of the study) to evaluate RO4929097 in combination with dexamethasone using one of the studied schedules. Blood, plasma, bone marrow, and tumor tissue samples may be collected at baseline and periodically during the first course for correlative lab and tumor studies, including pharmacokinetics.
After completion of study treatment, patients are followed up for up to 30 days.
*NOTE: This trial was intended to be Phase I/II, but the trial never continued to the Phase II portion.
Enrollment
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Inclusion and exclusion criteria
Inclusion Criteria:
Histologically confirmed malignancy (at diagnosis or relapse)
No B-cell precursor acute lymphoblastic lymphoma (ALL) or acute myeloid leukemia
No T-cell leukemia with CNS3 disease
Measurable or evaluable disease
Current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
Neurologic deficits in patients with CNS tumors must have been relatively stable for 1 week
No active CNS leukemia
Karnofsky performance status (PS) 50-100% (for patients > 16 years of age) or Lansky PS 50-100% (for patients ≤ 16 years of age)
Patients with solid tumors without bone marrow involvement must meet the following criteria:
Patients with known bone marrow metastatic disease must meet the above criteria and must not be known to be refractory to red cell or platelet transfusion
Patients with leukemia must meet the following criteria:
Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR a serum creatinine based on age/gender as follows:
Bilirubin (sum of conjugated and unconjugated) ≤ 1.5 times upper limit of normal (ULN) for age
ALT ≤ 110 U/L (for the purpose of this study, the ULN for ALT is 45 U/L)
Serum albumin ≥ 2 g/dL
No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia defined as < lower limit of normal despite adequate electrolyte supplementation
Baseline QTc < 450 msec
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective double-method contraception (i.e., one highly effective method and one additional effective method) for ≥ 4 weeks before, during, and for ≥ 12 months after completion of study treatment
Female patients may not donate ova during or after study treatment
Able to comply with the safety monitoring requirements of the study, in the opinion of the investigator
Able to swallow tablets and capsules
No known malabsorption syndrome or other condition that would interfere with intestinal absorption
No known serological positivity for hepatitis A, B, or C, no known history of liver disease, and no other forms of hepatitis or cirrhosis
No known HIV positivity
No uncontrolled infection
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097 or dexamethasone
Patients may not donate blood during or for ≥ 12 months after completion of study treatment
No hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia that is uncontrolled despite adequate electrolyte supplementation
No prior gamma-secretase inhibitor RO4929097
Fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy
More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea) (for patients with solid tumors, CNS tumors, or lymphomas)
Patients with T-cell leukemia must meet the following criteria:
At least 6 months since prior total-body irradiation (TBI), craniospinal radiotherapy, or radiotherapy to ≥ 50% of the pelvis
At least 6 weeks since other prior substantial bone marrow radiotherapy
At least 2 weeks since prior local palliative radiotherapy (small port)
At least 3 months since prior stem cell transplantation or rescue without TBI and no evidence of active graft-vs-host disease
At least 7 days since the completion of therapy with a biologic agent
At least 7 days or 3 half-lives, whichever is longer, since prior treatment with a monoclonal antibody
More than 7 days since prior growth factors that support platelet or white cell number or function
At least 7 days since prior corticosteroids
No other concurrent investigational drugs
No other concurrent anticancer agents including chemotherapy (except for hydroxyurea), radiotherapy, immunotherapy, or biologic therapy
No concurrent warfarin sodium (Coumadin®)
No concurrent medications that are strong inducers and/or inhibitors of CYP3A4
No concurrent medications or food that may interfere with the metabolism or gamma-secretase inhibitor RO4929097, including ketoconazole and fresh-squeezed grapefruit juice
Primary purpose
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Interventional model
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129 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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