Clinical trial NCT02630043: Trial of Tolcapone With Oxaliplatin for Neuroblastoma
Official title: A Phase I Trial of Tolcapone Alone and in Combination With Oxaliplatin in Patients With Relapsed or Refractory Neuroblastoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Neuroblastoma
Lead sponsor: Milton S. Hershey Medical Center
Sponsor class: OTHER
First posted: 2015-12-15
Enrollment: 5
Sex: ALL
Minimum age (years): 0
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this research study is to evaluate an investigational drug (Tolcapone) alone and in combination with oxaliplatin, for relapsed and refractory neuroblastoma. Tolcapone is approved by the U.S. Food and Drug Administration (FDA) for adults, but is an investigational drug in this study because it has not been approved in pediatrics for this indication. Oxaliplatin, although a drug approved by the FDA for other cancers, is investigational for treatment of neuroblastoma in this study. This study will look at the safety and tolerability of tolcapone in combination with oxaliplatin as well as the tumors response to this study drug.


Eligibility criteria: Inclusion Criteria:

1. Age: ≤ 21 years at the time of study entry.
2. Diagnosis: Histologic verification at either the time of original diagnosis or relapse of neuroblastoma.
3. Disease Status: Patients must have ONE of the following:

   * Any episode of recurrent disease following completion of aggressive multi-drug frontline therapy.
   * Any 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 protocols.
4. Measurable or evaluable disease, including at least one of the following: measureable tumor by CT or MRI; a positive MIBG, or PET scan; positive bone marrow biopsy/aspirate.
5. Current disease state must be one for which there is currently no known curative therapy
6. A negative urine or serum pregnancy test is required for female subjects of child bearing potential (onset of menses or ≥13 years of age).
7. Organ Function Requirements:

   * Subjects must have adequate liver function as defined by:

     * AST and ALT ≤ upper limit of normal
     * Serum bilirubin must be ≤ 2.0 mg/dl
   * Subjects must have adequate Bone Marrow function defined as:

For patients without bone marrow involvement:

• Peripheral absolute neutrophil count (ANC) \>750/uL

* Subjects must have adequate renal function
* 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 90 days 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 informed written consent. Assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion Criteria:

* Lansky score \<50%
* BSA (m2) of \<0.5
* Prior Therapy- Patients must have fully recovered from the acute toxic effects of all prior anti- cancer chemotherapy and be within the following timelines:

  * Myelosuppressive chemotherapy: Must not have received within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea).
  * Hematopoietic growth factors: At least 5 days since the completion of therapy with a growth factor.
  * 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.
  * Immunotherapy: At least 6 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.
  * XRT: At least 14 days since the last treatment except for radiation delivered with palliative intent to a non-target site.
  * 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.
* Subjects with CNS lesions are excluded
* Subjects with a history of depression, anxiety, or psychotic disorders (due to tolcapone adverse event profile).
* Subjects that are pregnant or breastfeeding an infant.
* Subjects that cannot swallow tablets.
* 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.

Primary outcomes:
measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability
timeFrame: 2 years
Secondary outcomes:
measure: Determine the Overall Response Rate (ORR) of Participants using RECIST criteria
timeFrame: 3 years
measure: Determine the Progression Free Survival (PFS) of Participants using days until progression
timeFrame: 3 years
measure: To evaluate the drug levels and pharmacokinetics (PK) of Tolcapone from blood samples at multiple time points within the first 24 hours on study based on Plasma half-life (t1/2).
timeFrame: 24 hours
measure: To evaluate the drug levels and pharmacokinetics (PK) of Tolcapone from blood samples at multiple time points within the first 24 hours on study based on Plasma clearance (Cl).
timeFrame: 24 hours
measure: To evaluate the drug levels and pharmacokinetics (PK) of Tolcapone from blood samples at multiple time points within the first 24 hours on study based on Vd.
timeFrame: 24 hours
measure: To evaluate the drug levels and pharmacokinetics (PK) of Tolcapone from blood samples at multiple time points within the first 24 hours on study based on Peak Plasma Concentration (Cmax)
timeFrame: 24 hours
measure: To evaluate the drug levels and pharmacokinetics (PK) of Tolcapone from blood samples at multiple time points within the first 24 hours on study based on Area Under the Curve (AUC).
timeFrame: 24 hours
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: San Diego
country: United States
facility: Rady Children's Hospital
state: California
city: Hartford
country: United States
facility: Connecticut Children's Hospital
state: Connecticut
city: Honolulu
country: United States
facility: Kapiolani Medical Center for Women and Children
state: Hawaii
city: Grand Rapids
country: United States
facility: Helen DeVos Children's Hospital
state: Michigan
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Medical Center
state: Missouri
city: Charlotte
country: United States
facility: Levine Children's Hospital
state: North Carolina
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center and Children's Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
Study officials:
affiliation: Spectrum Health Hospitals
name: Jessica Foley, MD
role: STUDY_CHAIR
References: