Phase I Study of Vorinostat in Combination With 13-Cis-retinoic Acid in Patients With Refractory/Recurrent Neuroblastoma
Overview
- Phase
- Phase 1
- Intervention
- Isotretinoin
- Conditions
- Localized Unresectable Neuroblastoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 29
- Locations
- 13
- Primary Endpoint
- Incidence of toxicity as assessed by NCI CTCAE v. 4.0
- Status
- Completed
- Last Updated
- 10 years ago
Overview
Brief Summary
This phase I trial is studying the side effects and the best dose of vorinostat when given together with isotretinoin to see how well it works in treating patients with high-risk refractory or recurrent neuroblastoma. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Isotretinoin may help vorinostat work better by making tumor cells more sensitive to the drug. Giving vorinostat together with isotretinoin may be an effective treatment for neuroblastoma.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of vorinostat pediatric suspension administered daily 4 times per week orally for two weeks, in combination with twice daily 13-cis-retinoic acid (\[cisRA\], isotretinoin) orally for 14 days to children with refractory or recurrent neuroblastoma. II. To define the toxicities of vorinostat administered in combination with cisRA. SECONDARY OBJECTIVES: I. To determine the pharmacokinetics of vorinostat given as a pediatric suspension. II. To describe the relationship of vorinostat pharmacokinetics to the occurrence of systemic toxicity. III. To determine the pharmacokinetics of cisRA given in combination with vorinostat. IV. To describe histone acetylation levels in peripheral blood mononuclear cells after different doses of vorinostat. V. To describe, within the context of a Phase I study, the response rate of vorinostat combined with cisRA in patients with recurrent/refractory neuroblastoma. VI. To describe the toxicity and response rate of vorinostat at the determined maximal tolerated dose combined with cisRA in patients ages 22-30 years of age at study entry with recurrent/refractory neuroblastoma. OUTLINE: This is a dose-escalation study of vorinostat. Patients receive isotretinoin orally (PO) twice daily (BID) on days 1-14, PO suspension\* of vorinostat once daily (QD) on days 1-4 of course 1, and capsules of vorinostat PO QD on days 1-4 and 8-11 of course 2 and subsequent courses. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. EXPANSION COHORT 1 (=\< 21 years of age): Once the maximum-tolerated dose (MTD) has been determined, patients are treated at that dose level as above. EXPANSION COHORT 2 (22-30 years of age): Patients receive isotretinoin as above and vorinostat at the MTD on days 1-3 and 8-10. After completion of study therapy, patients are followed up periodically. NOTE: \*Patients less than 10 years of age are encouraged to continue to use oral suspension beyond course 1.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must be =\< 21 years of age when registered on study for dose levels -1 to 5 and Expansion Cohort 1; patients age 22-30 years of age at time of study registration are eligible for Expansion Cohort 2
- •Patients must have a diagnosis of neuroblastoma either by histologic verification of neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines
- •Patients must have high-risk neuroblastoma
- •Patients must have at least ONE of the following:
- •Recurrent/progressive disease at any time; biopsy not required, even if partial response to intervening therapy
- •Refractory disease (i.e. less than a partial response to frontline therapy, including a minimum of 4 cycles of chemotherapy); no biopsy is required to document eligibility
- •Persistent disease after at least a partial response to frontline therapy (i.e. patient has had at least a partial response to frontline therapy but still has residual disease by metaiodobenzylguanidine \[MIBG\] scan, computed tomography \[CT\]/magentic resonance imaging \[MRI\], or bone marrow aspirates/biopsies); patients in this category are REQUIRED to have histologic confirmation of viable neuroblastoma from at least one residual site; tumor seen on routine bone marrow morphology is sufficient; bone marrow immunocytology alone is not sufficient for eligibility
- •Patients must have at least ONE of the following sites of disease (excluding those patients entered in the Expansion Cohort) :
- •Measurable tumor on MRI or CT scans or X-ray; measurable is defined \>= 20 mm in one dimension; for spiral CT defined as \>= 10 mm in one dimension; for patients with persistent disease, a biopsy of site seen on CT/MRI must have demonstrated viable neuroblastoma; if the lesion was radiated, then biopsy must be done \>= 4 weeks after radiation completed
- •MIBG scan with positive uptake at a minimum of one site; for patients with persistent disease, a biopsy of an MIBG positive site must have demonstrates viable neuroblastoma; if the lesion was radiated, then biopsy must be done \>= 4 weeks after radiation completed
Exclusion Criteria
- •Pregnancy, breast feeding, or unwillingness to use effective contraception during the study; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
- •Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
- •Patients with disease of any major organ system that would compromise their ability to withstand therapy
- •Patients with an active or uncontrolled infection; patients on prolonged antifungal therapy are still eligible if they are culture and biopsy negative in suspected radiographic lesions and meet other organ function criteria
- •Patients receiving enzyme-inducing anti-convulsants, pentamidine or azole anti-fungal therapy
- •Prior treatment with vorinostat combined with cisRA is not allowed; prior therapy with either vorinostat or cis-retinoic acid single agent or combined with alternative agents is allowed
- •Patients with a paraben allergy cannot take cisRA preparations containing this compound (i.e., Accutane, Sotret) but are eligible if they can take an alternate preparation without paraben
Arms & Interventions
Treatment (isotretinoin and vorinostat)
Patients receive isotretinoin PO BID on days 1-14, PO suspension\* of vorinostat QD on days 1-4 of course 1, and capsules of vorinostat PO QD on days 1-4 and 8-11 of course 2 and subsequent courses. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. EXPANSION COHORT 1 (=\< 21 years of age): Once the MTD has been determined, patients are treated at that dose level as above. EXPANSION COHORT 2 (22-30 years of age): Patients receive isotretinoin as above and vorinostat at the MTD on days 1-3 and 8-10.
Intervention: Isotretinoin
Treatment (isotretinoin and vorinostat)
Patients receive isotretinoin PO BID on days 1-14, PO suspension\* of vorinostat QD on days 1-4 of course 1, and capsules of vorinostat PO QD on days 1-4 and 8-11 of course 2 and subsequent courses. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. EXPANSION COHORT 1 (=\< 21 years of age): Once the MTD has been determined, patients are treated at that dose level as above. EXPANSION COHORT 2 (22-30 years of age): Patients receive isotretinoin as above and vorinostat at the MTD on days 1-3 and 8-10.
Intervention: Laboratory Biomarker Analysis
Treatment (isotretinoin and vorinostat)
Patients receive isotretinoin PO BID on days 1-14, PO suspension\* of vorinostat QD on days 1-4 of course 1, and capsules of vorinostat PO QD on days 1-4 and 8-11 of course 2 and subsequent courses. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. EXPANSION COHORT 1 (=\< 21 years of age): Once the MTD has been determined, patients are treated at that dose level as above. EXPANSION COHORT 2 (22-30 years of age): Patients receive isotretinoin as above and vorinostat at the MTD on days 1-3 and 8-10.
Intervention: Pharmacological Study
Treatment (isotretinoin and vorinostat)
Patients receive isotretinoin PO BID on days 1-14, PO suspension\* of vorinostat QD on days 1-4 of course 1, and capsules of vorinostat PO QD on days 1-4 and 8-11 of course 2 and subsequent courses. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. EXPANSION COHORT 1 (=\< 21 years of age): Once the MTD has been determined, patients are treated at that dose level as above. EXPANSION COHORT 2 (22-30 years of age): Patients receive isotretinoin as above and vorinostat at the MTD on days 1-3 and 8-10.
Intervention: Vorinostat
Outcomes
Primary Outcomes
Incidence of toxicity as assessed by NCI CTCAE v. 4.0
Time Frame: Up to 3 years
All toxicities observed will be summarized in terms of type (organ affected or laboratory determination), severity (by NCI CTCAE), and attribution. Tables will be created to summarize theses toxicities and side effects by dose level and by course.
MTD of vorinostat, determined according to incidence of dose-limiting toxicities graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0
Time Frame: 28 days
Secondary Outcomes
- Survival(Up to 3 years)
- Time-to-failure(Up to 3 years)
- Best response, assessed using Response Evaluation Criteria in Solid Tumors (RECIST)(Up to 3 years)