Randomized Efficacy Study of TPI 287 to Treat Primary Refractory or Early Relapsed Neuroblastoma

Study Overview
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Brief Summary
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The purpose of this research study is to evaluate a new investigational drug (TPI 287) for early relapsed neuroblastoma. An investigational drug is one that has not yet been approved by the Food and Drug Administration. This investigational drug is called TPI 287. This study will look at the tumor's response to the study drug, TPI 287, in combination with Irinotecan and Temozolomide versus the combination of Irinotecan and Temozolomide alone. This study will also evaluate the safety and tolerability of the study drug, TPI 287.

Official Title
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A Randomized, Phase I/II Trial of Irinotecan and Temozolomide Compared to Irinotecan and Temozolomide in Combination With TPI 287 in Patients With Primary Refractory or Early Relapsed Neuroblastoma

Conditions
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Neuroblastoma

Intervention / Treatment
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* Drug: TPI 287
* Drug: Temozolomide
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have histologically proven Neuroblastoma and confirmation of primary refractory or recurrent disease with histologic confirmation at diagnosis or at the time of recurrence/progression. Subjects must have primary refractory or have early relapse disease (early relapse disease is defined as having received ≤ one or two relapse therapies). Subjects must be age >12 months and diagnosed before the age of 21 years Measurable disease, including at least one of the following: Measurable tumor >10 mm by CT or MRI Positive bone marrow biopsy/aspirate Positive MIBG Current disease state must be one for which there is currently no known curative therapy Lansky Play Score or Karnofsky scale must be more than 30 Subjects without bone marrow metastases must have an ANC > 750/μl and platelet count >50,000/μl Adequate Renal Function Defined As Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or A serum creatinine based on age/gender table Adequate liver function must be demonstrated, defined as: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age SGPT (ALT) < 10 x upper limit of normal (ULN) for age SGOT (AST) < 10x upper limit of normal (ULN) for age No other significant organ toxicity defined as >Grade 2 by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE V4.0- http://ctep.cancer.gov/forms/CTCAEv4.pdf) A negative urine pregnancy test is required for female participants of child bearing potential (≥13 years of age or after onset of menses) Both male and female post-pubertal study subjects need to agree to use one of the more effective birth control methods during treatment and for six months after treatment is stopped. These methods include total abstinence (no sex), oral contraceptives (the pill), an intrauterine device (IUD), levonorgestrol implants (Norplant), or medroxyprogesterone acetate injections (Depo-provera shots). If one of these cannot be used, contraceptive foam with a condom is recommended. Informed Consent: All subjects and/or legal guardians must sign written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines Subjects may have received microtubulin inhibitors during previous therapies. Subjects may have received any number of prior biological therapies. Exclusion Criteria: Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from the effects of prior chemotherapy (hematological and bone marrow suppression effects), generally at least 3 weeks from the most recent administration (6 weeks for nitrosoureas). Subjects may not have received more than 1 cycle of Irinotecan and Temozolomide as previous relapse therapy. Subjects who have received any myeloablative therapy within the previous 2 months. Subjects receiving any investigational drug concurrently Subjects with serious infection or a life-threatening illness (unrelated to tumor) that is > Grade 2 (NCI CTCAE V4.0), or active, serious infections requiring parenteral antibiotic therapy. Subjects with any other medical condition, including malabsorption syndromes, mental illness or substance abuse, deemed by the Investigator to be likely to interfere with the interpretation of the results or which would interfere with a subject's ability to sign or the legal guardian's ability to sign the informed consent, and subject's ability to cooperate and participate in the study Subjects with known hypersensitivity to any of the components of the drugs to be administered on study. Subjects who have previously been treated with TPI 287.

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A- Temozolomide and Irinotecan<br>Oral (PO) Temozolomide at a dose of 100mg/m2 on days 1-5 of each 28 day cycle. Intravenous (IV) Irinotecan at a dose of 10mg/m2 on days 1-5 and 8-12 of each 28 day cycle. Patients who show progression on the I+TMZ arm may crossover to the I+TMZ+TPI 287 arm at anytime during cycles 1 to 6. If there is evidence of progression after completion of the I+TMZ arm (after completion of cycle 6) then the patient will have been considered to have completed therapy and is not eligible for the crossover. | Drug: Temozolomide<br>* Oral (PO) Temozolomide at a dose of 100mg/m2 on days 1-5 of each 28 day cycle<br>* Other names: temodar;Drug: Irinotecan<br>* Intravenous (IV) Irinotecan at a dose of 10mg/m2 on days 1-5 and 8-12 of each 28 day cycle.<br>|
| Experimental: Arm B- Temozolomide/Irinotecan + TPI 287<br>Cycle 1 to 6: Irinotecan and Temozolomide in combination with TPI 287 Intravenous (IV) TPI 287 at a dose of 125 mg/m2 on Days 1, 8 and 15 of a 28-day cycle. Oral (PO) Temozolomide at a dose of 100mg/m2 on days 1-5 of each 28 day cycle. Intravenous (IV) Irinotecan at a dose of 10mg/m2 on days 1-5 and 8-12 of each 28 day cycle. | Drug: TPI 287<br>* Subjects will receive six cycles of intravenous (IV) TPI 287 at a dose of 125 mg/m2 on Days 1, 8 and 15 of a 28-day cycle.<br>Drug: Temozolomide<br>* Oral (PO) Temozolomide at a dose of 100mg/m2 on days 1-5 of each 28 day cycle<br>* Other names: temodar;Drug: Irinotecan<br>* Intravenous (IV) Irinotecan at a dose of 10mg/m2 on days 1-5 and 8-12 of each 28 day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | To determine the safety and tolerability of TPI 287 in combination with Irinotecan and Temozolomide (TPI+I+TMZ) in pediatric and young adult patients with primary refractory or recurrent Neuroblastoma. Phase I patients were all enrolled to receive TPI 287. Phase 2 is where randomization began. Patients were different patients than the Phase 1 patients. Below all patients that received TPI 287 are included in the TPI 287 group. This includes Phase I patients and the Phase 2 patients randomized to TPI 287. | 6 months | 
| Overall Response Rate (ORR) of Participants Using RECIST Criteria | Phase I portion of trial- All patients enrolled to recieve TPI+I+TMZ. These patients will be added to the Phase II patients that were randomized to Arm B- Arm with TPI 287 (recieved same tx as Phase I participatns). Phase II portion of trial- TPatients enrolled to this portion (different patients than enrolled to Phase 1) were randomized to Arm A: I+TMZ OR Arm B: TPI+I+TMZ Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of TPI 287 in the Phase I Population of This Trial. | To evaluate the drug levels and pharmacokinetics (PK) of TPI 287 from blood samples at multiple time points within the first 24 hours on study. | 1 year | 
| Measure Quality of Life of Children Receiving TPI287 Using PedsQL Questionnaires | Evaluate the impact on QOL of children receiving TPI+I+TMZ | 3 years | 
| Progression Free Survival (PFS) of Participants Using Days Until Progression | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | 3 years | 
| Median Overall Survival (OS) of Participants | To determine OS and clinical benefit (CR/PR/SD) in this population | 3 years |