Neuroblastoma Recurrent
Conditions
Brief summary
The purpose of this research study is to evaluate an investigational drug (DFMO) in combination with bortezomib, for relapsed and refractory neuroblastoma. DFMO is an investigational drug because it has not been approved by the U.S. Food and Drug Administration (FDA). This study will look at the safety and tolerability of DFMO in combination with bortezomib as well as the tumors response to this study drug.
Interventions
DRUGBortezomib
DRUGDFMO
Sponsors
Beat NB Cancer Foundation
Because of Ezra
K C Pharmaceuticals Inc.
Giselle Sholler
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
* Age: ≤ 21 years at the time of diagnosis. * Diagnosis: Histologic verification at either the time of original diagnosis or relapse of neuroblastoma. * Disease Status: For the purposes of this study, aggressive multidrug chemotherapy is defined as chemotherapy including 2 or more agents that must include an alkylating agent and a platinum-containing compound. Patients must have one of the following: * First episode of recurrent disease following completion of aggressive multi-drug frontline therapy. * First episode of progressive disease during aggressive multi-drug frontline therapy. * Primary resistant/refractory disease detected at the conclusion of at least 4 cycles of aggressive multidrug induction chemotherapy on or according to a high-risk neuroblastoma protocol (examples include Children's Oncology Group trials: A3973, ANBL0532, ANBL09P1, etc.). * Measurable or evaluable disease, including at least one of the following: Measureable tumor by CT or MRI; or A positive meta-iodobenzylguanidine (MIBG) or positron emission computed tomography (PET) scan; or Positive bone marrow biopsy/aspirate. * Current disease state must be one for which there is currently no known curative therapy or no additional therapies proven to prolong survival with an acceptable quality of life. * A negative urine pregnancy test is required for female subjects of child bearing potential (onset of menses or ≥13 years of age). * Organ Function Requirements: 1. Subjects must have adequate liver function as defined by: * AST (aspartate aminotransferase) and alanine aminotransferase (ALT) \<5x upper limit of normal * Serum bilirubin must be ≤ 2.0 mg/dl 2. Subjects must have adequate Bone Marrow function defined as: For patients without bone marrow involvement: * Peripheral absolute neutrophil count (ANC) ≤ 750/uL * Platelet count 50,000/uL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment. Exception: Patients that are platelet dependent due to previous extensive treatment- e.g. - MIBG therapy). * Hemoglobin ≥ 8.0 g/dL (may receive red blood cell transfusions) Patients known to have bone marrow involvement with neuroblastoma are eligible provided that minimum ANC and platelet count criteria are met but are not evaluable for hematological toxicity. * Subjects must have adequate renal function defined as: Serum creatinine based on age/gender. * Informed Consent: All subjects and/or legal guardians must sign informed written consent. Assent, when appropriate, will be obtained according to institutional guidelines.
Exclusion criteria
* Lansky score \<50% * BSA (body surface area) body surface body surface m2 of \<0.25 * Prior Therapy- Patients must have fully recovered from the acute toxic effects of all prior anti- cancer chemotherapy and be within the following timelines: 1. Myelosuppressive chemotherapy: Must not have received within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea). 2. Hematopoietic growth factors: At least 5 days since the completion of therapy with a growth factor. 3. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. 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. 4. Immunotherapy: At least 6 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines. 5. Monoclonal antibodies: At least 7 days or 3 half-lives, whichever is longer, must have elapsed since prior treatment with a monoclonal antibody. 6. Radiotherapy: At least 14 days since the last treatment except for radiation delivered with palliative intent to a non-target site. 7. Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease and ≥ 2 months must have elapsed since transplant. * Investigational Drugs: Subjects who have received another investigational drug within the last 14 days are excluded from participation. * Infection: Subjects who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator. * Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Adverse Events were collected starting with the date of the first dose of study drug until 30 days after last dose of study drug, ongoing related adverse events were continued to be followed until resolution, on average 6 months. | Phase I- To determine the safety and tolerability of DFMO in combination with bortezomib at 3 dose levels of DFMO: 1500mg/m2 twice daily, 2000mg/m2 twice daily, and 2500mg/m2 twice daily in subjects with relapsed or refractory neuroblastoma who receive one full cycle of this dose. Phase II- Study did not enroll to Phase II. Study completed at end of Phase I. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Followed until off therapy, generally 1 year | To determine the overall response rate (ORR) by the presence of radiologically assessable disease by cross-sectional imaging and in MIBG (meta-iodobenzylguanidine) or PET (positron emission computed tomography) scans. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI imaging and/or by MIBG or PET scans: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the disease measurements for measurable lesions, Stable Disease, Neither sufficient decrease to qualify for PR or sufficient increase to qualify for PD from study entry. Overall Response (OR) = CR + PR. |
| Determine the Progression Free Survival (PFS) of Participants Using Days Until Progression | From date of start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year | Time to progression (PFS), defined as the period from the start of the treatment until the criteria for progression are met taking as reference the screening measurements. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the disease measurements for measurable lesions, taking as reference the smallest disease measurement recorded since the start of treatment (nadir), and minimum 5 mm increase over the nadir or the appearance of one or more new lesions or appearance of positive bone marrow. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I: DFMO 1500 mg/m^2 Subjects will take DFMO by mouth 2 times a day for each day of a 21 day cycle and Bortezomib will be given by IV push on days 1, 4, and 8 of each 21 day cycle. | 3 |
| Phase I: DFMO 2000 mg/m^2 Subjects will take DFMO by mouth 2 times a day for each day of a 21 day cycle and Bortezomib will be given by IV push on days 1, 4, and 8 of each 21 day cycle. | 7 |
| Phase I: DFMO 2500 mg/m^2 Subjects will take DFMO by mouth 2 times a day for each day of a 21 day cycle and Bortezomib will be given by IV push on days 1, 4, and 8 of each 21 day cycle. | 6 |
| Phase 2 The highest tolerated DFMO dose from the Phase I dose escalation will be used for the Phase II portion of the study. Subjects will receive oral DFMO twice daily on each day of this 21-day cycle along with Bortezomib and Etoposide. | 0 |
| Total | 16 |
Baseline characteristics
| Characteristic | Phase I: DFMO 1500 mg/m^2 | Phase I: DFMO 2000 mg/m^2 | Phase I: DFMO 2500 mg/m^2 | Phase 2 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 7 Participants | 6 Participants | 0 Participants | 16 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 10 years | 7.1 years | 10 years | — | 8.75 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | — | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 7 Participants | 4 Participants | — | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | — | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | — | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | — | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | — | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 7 Participants | 3 Participants | — | 13 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 2 Participants | — | 5 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 4 Participants | — | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 7 | 1 / 6 |
| other Total, other adverse events | 2 / 3 | 1 / 7 | 3 / 6 |
| serious Total, serious adverse events | 0 / 3 | 1 / 7 | 1 / 6 |
Outcome results
Primary
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Phase I- To determine the safety and tolerability of DFMO in combination with bortezomib at 3 dose levels of DFMO: 1500mg/m2 twice daily, 2000mg/m2 twice daily, and 2500mg/m2 twice daily in subjects with relapsed or refractory neuroblastoma who receive one full cycle of this dose. Phase II- Study did not enroll to Phase II. Study completed at end of Phase I.
Time frame: Adverse Events were collected starting with the date of the first dose of study drug until 30 days after last dose of study drug, ongoing related adverse events were continued to be followed until resolution, on average 6 months.
Population: All subjects that took at least one dose of DFMO
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I: DFMO 1500 mg/m^2 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 2 Participants |
| Phase I: DFMO 2000 mg/m^2 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 1 Participants |
| Phase I: DFMO 2500 mg/m^2 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 3 Participants |
Secondary
Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria
To determine the overall response rate (ORR) by the presence of radiologically assessable disease by cross-sectional imaging and in MIBG (meta-iodobenzylguanidine) or PET (positron emission computed tomography) scans. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI imaging and/or by MIBG or PET scans: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the disease measurements for measurable lesions, Stable Disease, Neither sufficient decrease to qualify for PR or sufficient increase to qualify for PD from study entry. Overall Response (OR) = CR + PR.
Time frame: Followed until off therapy, generally 1 year
Population: Analyzed population only includes evaluable subjects, defined as subjects that made it to an evaluation time point (disease evaluation scans), or had a documented progression of disease prior to evaluation time point.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I: DFMO 1500 mg/m^2 | Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Complete Response | 0 Participants |
| Phase I: DFMO 1500 mg/m^2 | Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Progressive Disease | 1 Participants |
| Phase I: DFMO 1500 mg/m^2 | Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Stable Disease | 1 Participants |
| Phase I: DFMO 1500 mg/m^2 | Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Mixed Response | 0 Participants |
| Phase I: DFMO 1500 mg/m^2 | Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Partial Response | 1 Participants |
| Phase I: DFMO 2000 mg/m^2 | Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Mixed Response | 1 Participants |
| Phase I: DFMO 2000 mg/m^2 | Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Complete Response | 0 Participants |
| Phase I: DFMO 2000 mg/m^2 | Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Partial Response | 0 Participants |
| Phase I: DFMO 2000 mg/m^2 | Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Stable Disease | 2 Participants |
| Phase I: DFMO 2000 mg/m^2 | Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Progressive Disease | 2 Participants |
| Phase I: DFMO 2500 mg/m^2 | Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Partial Response | 0 Participants |
| Phase I: DFMO 2500 mg/m^2 | Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Mixed Response | 0 Participants |
| Phase I: DFMO 2500 mg/m^2 | Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Progressive Disease | 3 Participants |
| Phase I: DFMO 2500 mg/m^2 | Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Complete Response | 0 Participants |
| Phase I: DFMO 2500 mg/m^2 | Determine the Overall Response Rate (ORR) of Participants Using RECIST Criteria | Stable Disease | 2 Participants |
Secondary
Determine the Progression Free Survival (PFS) of Participants Using Days Until Progression
Time to progression (PFS), defined as the period from the start of the treatment until the criteria for progression are met taking as reference the screening measurements. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the disease measurements for measurable lesions, taking as reference the smallest disease measurement recorded since the start of treatment (nadir), and minimum 5 mm increase over the nadir or the appearance of one or more new lesions or appearance of positive bone marrow.
Time frame: From date of start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year
Population: Analyzed population only includes evaluable subjects, defined as subjects that made it to an evaluation time point (disease evaluation scans), or had a documented progression of disease prior to evaluation time point.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: DFMO 1500 mg/m^2 | Determine the Progression Free Survival (PFS) of Participants Using Days Until Progression | 108.3 Days |
| Phase I: DFMO 2000 mg/m^2 | Determine the Progression Free Survival (PFS) of Participants Using Days Until Progression | 51.2 Days |
| Phase I: DFMO 2500 mg/m^2 | Determine the Progression Free Survival (PFS) of Participants Using Days Until Progression | 61.8 Days |