Neuroblastoma
Conditions
Brief summary
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.
Interventions
DRUGTPI 287
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.
DRUGTemozolomide
Oral (PO) Temozolomide at a dose of 100mg/m2 on days 1-5 of each 28 day cycle
DRUGIrinotecan
Intravenous (IV) Irinotecan at a dose of 10mg/m2 on days 1-5 and 8-12 of each 28 day cycle.
Sponsors
Cortice Biosciences, Inc.
Giselle Sholler
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Months to 21 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 6 months | 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. |
| Overall Response Rate (ORR) of Participants Using RECIST Criteria | 3 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK) of TPI 287 in the Phase I Population of This Trial. | 1 year | 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. |
| Measure Quality of Life of Children Receiving TPI287 Using PedsQL Questionnaires | 3 years | Evaluate the impact on QOL of children receiving TPI+I+TMZ |
| Progression Free Survival (PFS) of Participants Using Days Until Progression | 3 years | 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 |
| Median Overall Survival (OS) of Participants | 3 years | To determine OS and clinical benefit (CR/PR/SD) in this population |
Countries
United States
Participant flow
Pre-assignment details
Phase 1- All patients assigned to TPI 287 group. Randomization began in Phase 2- Arm A patients were allowed to cross over to Arm B during cycles 1-6 if they experienced progression. 0 (zero) Arm A patients crossed over to Arm B on this study.
Participants by arm
| Arm | Count |
|---|---|
| Arm A- Temozolomide and Irinotecan 1. Oral (PO) Temozolomide at a dose of 100mg/m2 on days 1-5 of each 28 day cycle.
2. 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.
Temozolomide: Oral (PO) Temozolomide at a dose of 100mg/m2 on days 1-5 of each 28 day cycle
Irinotecan: Intravenous (IV) Irinotecan at a dose of 10mg/m2 on days 1-5 and 8-12 of each 28 day cycle. | 2 |
| Arm B- Temozolomide/Irinotecan + TPI 287 Cycle 1 to 6: Irinotecan and Temozolomide in combination with TPI 287
1. Intravenous (IV) TPI 287 at a dose of 125 mg/m2 on Days 1, 8 and 15 of a 28-day cycle.
2. Oral (PO) Temozolomide at a dose of 100mg/m2 on days 1-5 of each 28 day cycle.
3. Intravenous (IV) Irinotecan at a dose of 10mg/m2 on days 1-5 and 8-12 of each 28 day cycle.
TPI 287: 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.
Temozolomide: Oral (PO) Temozolomide at a dose of 100mg/m2 on days 1-5 of each 28 day cycle
Irinotecan: Intravenous (IV) Irinotecan at a dose of 10mg/m2 on days 1-5 and 8-12 of each 28 day cycle. | 12 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Phase I | Adverse Event | 0 | 1 |
| Phase I | Lack of Efficacy | 0 | 4 |
| Phase I | Withdrawal by Subject | 0 | 1 |
| Phase II | Lack of Efficacy | 2 | 1 |
| Phase II | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Arm A- Temozolomide and Irinotecan | Arm B- Temozolomide/Irinotecan + TPI 287 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 2 Participants | 11 Participants | 13 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 12 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 8 Participants | 10 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 0 Participants | 9 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 12 | 0 / 2 |
| serious Total, serious adverse events | 3 / 12 | 0 / 2 |
Outcome results
Primary
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.
Time frame: 6 months
Population: This group includes the 8 patients enrolled to phase 1 TPI 287 portion of the study plus the 4 additional patients randomized to TPI 287 in the Phase 2 portion = 12 patients total that received TPI 287 on this study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TPI 287 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 7 participants |
| Arm A- TMZ + Irinotecan Only | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 0 participants |
Primary
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.
Time frame: 3 years
Population: 8 enrolled to Phase 1: two were non-evaluable =6 move to analysis. Another 4 randomized to Arm B with TPI 287 in Phase 2=10 evaluable in TPI 287 analysis.~2 subjects were enrolled in the Phase 2 randomized portion of the trial to Arm A- without TPI 287. This makes 2 evaluable subjects in this analysis population (did not receive TPI 287).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TPI 287 | Overall Response Rate (ORR) of Participants Using RECIST Criteria | 0 participants |
| Arm A- TMZ + Irinotecan Only | Overall Response Rate (ORR) of Participants Using RECIST Criteria | 2 participants |
Secondary
Measure Quality of Life of Children Receiving TPI287 Using PedsQL Questionnaires
Evaluate the impact on QOL of children receiving TPI+I+TMZ
Time frame: 3 years
Population: QOL's not collected due to early closure of study. Data not collected or analyzed threfore no data exists.
Secondary
Median Overall Survival (OS) of Participants
To determine OS and clinical benefit (CR/PR/SD) in this population
Time frame: 3 years
Population: Not evaluated due to early closure. Study data does not exist.
Secondary
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.
Time frame: 1 year
Population: PK's not run due to early closure of study. Data not collected or analyzed threfore no data exists.
Secondary
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
Time frame: 3 years
Population: Arm A- 2 subjects randomized to TMZ+I. Arm B- 6 evalubale patients in Phase 1 + 4 evaluable patients in Phase 2- all received TMZ+I+TPI
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TPI 287 | Progression Free Survival (PFS) of Participants Using Days Until Progression | 22 Days |
| Arm A- TMZ + Irinotecan Only | Progression Free Survival (PFS) of Participants Using Days Until Progression | 125 Days |