Sirolimus With Cyclophosphamide and Topotecan for Pediatric/Adolescent Relapsed and Refractory Solid Tumors

NCT01670175 | Completed Phase 1 DMC

• 2 other identifiers: UCSF CC# 12083IRB # 12-09399
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase I study of the combination of three drugs: sirolimus, cyclophosphamide, and topotecan. This is the first study to evaluate the safety and clinical activity of the combination of oral sirolimus, oral cyclophosphamide and oral topotecan in pediatric and young adult patients with relapsed and refractory solid tumors. In this phase I study, the mTOR inhibitor sirolimus will be administered in combination with oral cyclophosphamide and oral topotecan to children with relapsed or refractory solid tumors. The primary aim of this study is to recommend a phase II dose schedule and describe the toxicity of this combination. Myelosuppression will be a targeted toxicity.

Conditions

Malignant Solid Tumor; Childhood Solid Tumor

Keywords

Histologic verification of solid tumor, including lymphomas; Original diagnosis or relapse

Outcome Measures

Primary Outcomes (1)

• Dose Limiting Toxicity

  Define the dose limiting toxicities to recommend a Phase 2 trough concentration of sirolimus when administered on a protracted schedule in combination with oral topotecan and oral cyclophosphamide. Evaluations done during first Cycle to assess/define DLT: Physical exams, vitals, blood tests: CBC, CMB, coagulation-PT, LDH, D-dimer, peripheral smear, urine glucose, performance evaluations. All toxicities observed will be summarized in terms of type (organ affected or laboratory determination), severity (by NCI CTCAE v 4.0), and attribution. The MTD is the highest dose level tested at which 0/6 or 1/6 patients experience DLT that is possibly, probably, or definitely related to the study drug(s) with at least 2/3 or 2/6 patients encountering DLT at the next higher dose. If 0/6 or 1/6 patients experience DLT at the highest dose level (dose level 3), then that dose level will be called the MTD.

  During the first 28-day Cycle

Secondary Outcomes (3)

• Antitumor Activity

  At the end of the first 28-day Cycle

• Biologic efects of drug combination

  During the first 28-day Cycle

• Antiangiogenic properties of drug combination

  During the first 28-day Cycle

Other Outcomes (1)

• Correlative endpoints

  After one cycle (28 days) of therapy

Study Arms (1)

Sirolimus, Cyclophosphamide, Topotecan

EXPERIMENTAL

Sirolimus, Cyclophosphamide, Topotecan Patients accrued to dose levels in cohorts of 3 (3+3 design). Patients will receive daily oral sirolimus and cyclophosphamide days 1-21 in 28-day cycle, combined with oral topotecan given on days 1-14. Sirolimus will be dosed based on steady-state plasma trough concentrations.

Drug: Sirolimus, Cyclophosphamide, Topotecan

Interventions

Sirolimus, Cyclophosphamide, Topotecan DRUG

Dosing of cyclophosphamide and topotecan will be 25 mg/m2/dose and 0.8 mg/ m2 /dose respectively for dose levels 1 and 2. Level 3 dosing will escalate cyclophosphamide to 50 mg/ m2/dose. If level 1 dosing not tolerated, patients will be enrolled in level -1 cohort with cyclophosphamide and sirolimus administered only on days 1-14. If level -1 not tolerated, patients will be enrolled in level -2 with topotecan administration limited to days 1-7.

Sirolimus, Cyclophosphamide, Topotecan

Eligibility Criteria

• Age: Up to 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age: Patients must be \> than 12 months and 30 years of age at the time of study enrollment.
• Diagnosis: Patients must have had histologic verification of solid tumor, including lymphomas, at original diagnosis or relapse except in patients with intrinsic brain stem tumors, patients with optic pathway gliomas, and patients with pineal tumors and elevations of serum or CSF alpha-fetoprotein or beta-HCG.
• Disease Status: Patients must have either measurable or evaluable disease
• Therapeutic Options: Patient's current disease state must be one for which there is no known curative therapy.
• Performance Level: Karnofsky 50% for patients \> 16 years of age and Lansky 50 for patients 16 years of age. Note: Neurologic deficits in patients with CNS tumors must have been relatively stable for a minimum of 1 week prior to study enrollment. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. (Appendix I)
• Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior anticancer chemotherapy.
• Myelosuppressive chemotherapy: Patients must not have received myelosuppressive therapy within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea).
• Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
• Biologic (anti-neoplastic agent): At least 7 days must have passed after the last treatment with a biologic agent. For agents that have known adverse events occurring beyond 7 days from administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
• Immunotherapy: At least 4 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines.
• Monoclonal antibodies: At least 7 days or 3 half-lives, whichever is longer, must have elapsed since prior treatment with a monoclonal antibody. Please see Appendix III for a list of half-lives for common monoclonal antibodies.
• XRT: ≥ 2 weeks must have elapsed for local palliative XRT (small port) and enrollment on study. At least 24 weeks must have elapsed since prior Total Body Irradiation (TBI), radiation to ≥50% of pelvis, or craniospinal radiation; ≥ 6 weeks must have elapsed if the patient has received other substantial BM radiation; \> 6 weeks for prior MIBG therapy; For patients with only one site of measurable or evaluable disease, radiation must not have been given to that site unless that site has demonstrated clear progression after radiation or at least 2 months have elapsed since radiation and their remains evidence of viable tumor on biopsy, FDG pet scan or MIBG scan.
• Stem Cell Transplant (SCT): Patients are eligible 12 weeks after myeloablative therapy with autologous stem cell transplant (timed from start of protocol therapy). Patients must meet adequate bone marrow function definition (see organ function requirements below) post-myeloablative therapy. Patients who received stem cell reinfusion following non-myeloablative therapy are eligible once they meet peripheral blood count criteria in 6.1.7.1 Patients status post-allogeneic stem cell transplant are excluded unless they are \>1 year post transplant, have been off all immunosuppressive therapy for more than 3 months and do not have active GVHD.
• Prior treatment with sirolimus, cyclophosphamide or topotecan: Patients previously treated with any of these drugs as single agents will be eligible for this study. Patients previously treated with two of the three drugs will also be eligible, however patients previously treated with all three agents in combination will not be eligible.
• Patients previously treated with sirolimus analogues (e.g. Temsirolimus, everolimus, or ridaforolimus) are also eligible.

You may not qualify if:

• Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
• Concomitant Medications:
• Corticosteroids: Patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the prior 7 days.
• Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible.
• Enzyme-inducing anticonvulsants: Patients who are currently receiving enzyme inducing anticonvulsants are not eligible.
• CYP3A4 active agents: Patients must not be receiving any of the following potent CYP3A4 inducers or inhibitors: erythromycin, clarithromycin, ketoconazole, azithromycin, itraconazole, grapefruit juice or St. John's Wort. A list of other known CYP3A4 inducers and inhibitors that should be avoided during study therapy is included in Appendix V.
• Infection: Patients who have an active or uncontrolled infection are not eligible. 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 who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
• Patients with history of allergic reactions attributed to compounds of similar composition to sirolimus, cyclophosphamide, or topotecan are not eligible.

Sponsors & Collaborators

• University of California, San Francisco: lead
• Hyundai Hope On Wheels: collaborator

Study Sites (1)

UCSF Benioff Children's Hospital

San Francisco, California, 94143, United States

Location

MeSH Terms

Conditions

Recurrence

Interventions

Sirolimus; Cyclophosphamide; Topotecan

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Camptothecin; Alkaloids; Heterocyclic Compounds

Study Officials

• Steven Dubois, MD

  Dana-Farber Cancer Institute

  STUDY CHAIR

• Katherine Matthay, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 17, 2012
• First Posted: August 22, 2012
• Study Start: August 1, 2012
• Primary Completion: September 1, 2016
• Study Completion: September 1, 2016
• Last Updated: June 21, 2017

Record last verified: 2017-06

Locations

US (1)