Clinical Trials /

Erlotinib in Combination With Temozolomide in Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors

NCT02689336

Description:

This study proposes to treat patients with the combination of erlotinib and temozolomide. Patients with relapsed, recurrent, refractory, or high risk malignancies whose tumors possess a non-synonymous mutation in EGFR, ERBB2, or JAK2V617F (JAK2) will be eligible for the study. Very few phase 2 clinical trials have been performed in pediatrics using targeted agents in combination with conventional chemotherapy agents. Furthermore, since some combinations such as the combination of this study (erlotinib and temozolomide) have shown additive/synergistic effects in preclinical studies, therapy selecting for those patients who possess mutations targeted by the TKI of the study, may unveil activity that has not been previously observed. Thus, the investigators hope to determine whether the addition of additive/synergistic chemotherapy will increase efficacy of target agent and/or increase tumor susceptibility to targeted agent resulting in increased anti-tumor activity.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Erlotinib in Combination With Temozolomide in Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors
  • Official Title: Phase 2 Clinical Trial Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors With the Genomically-Targeted Agent Erlotinib in Combination With Temozolomide

Clinical Trial IDs

  • ORG STUDY ID: 201604002
  • NCT ID: NCT02689336

Conditions

  • Glioma
  • Rhabdomyosarcoma
  • Osteosarcoma
  • Medulloblastoma
  • Neuroectodermal Tumor
  • Ependymoma
  • Ewing's Sarcoma
  • Wilms Tumor

Interventions

DrugSynonymsArms
ErlotinibTarcevaErlotinib and Temozolomide
TemozolomideTemodar®Erlotinib and Temozolomide

Purpose

This study proposes to treat patients with the combination of erlotinib and temozolomide. Patients with relapsed, recurrent, refractory, or high risk malignancies whose tumors possess a non-synonymous mutation in EGFR, ERBB2, or JAK2V617F (JAK2) will be eligible for the study. Very few phase 2 clinical trials have been performed in pediatrics using targeted agents in combination with conventional chemotherapy agents. Furthermore, since some combinations such as the combination of this study (erlotinib and temozolomide) have shown additive/synergistic effects in preclinical studies, therapy selecting for those patients who possess mutations targeted by the TKI of the study, may unveil activity that has not been previously observed. Thus, the investigators hope to determine whether the addition of additive/synergistic chemotherapy will increase efficacy of target agent and/or increase tumor susceptibility to targeted agent resulting in increased anti-tumor activity.

Trial Arms

NameTypeDescriptionInterventions
Erlotinib and TemozolomideExperimentalErlotinib is an oral drug that will be administered on an outpatient basis at a dose of 85 mg/m^2/dose once a day continuously (every day of a 28-day cycle) Temozolomide is an oral drug that will be administered on an outpatient basis at a dose of 180mg/m2/dose once a day on Days 1-5 of a 28-day cycle.
  • Erlotinib
  • Temozolomide

Eligibility Criteria

        Inclusion Criteria:

          -  One to 21 years of age

          -  Relapsed, recurrent, or refractory malignancy. All solid tumor diagnoses will be
             eligible.

               -  Pathologic confirmation of the diagnosis either at original diagnosis or
                  recurrence.

               -  Known non-synonymous mutation in the following genes: EGFR, ERBB2, or JAK2V617F
                  (JAK2). Genomic sample preferably from relapse, but may be from other stage of
                  treatment if relapse sample is not reasonably obtainable. Genetic analysis for
                  determination of eligibility occurs as part of routine care and is not being
                  performed specifically for the purposes of this study.

          -  Measurable disease defined as lesions that can be accurately measured in at least one
             dimension (longest diameter to be recorded) as ≥ 10 mm with CT or MRI scan, as ≥ 20 mm
             by chest x-ray, or ≥ 10 mm with calipers by clinical exam.

          -  Prior therapy as follows:

               -  Patients must have fully recovered from the acute toxic effects of all prior
                  chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

               -  Myelosuppressive chemotherapy: Patients must not have received myelosuppressive
                  chemotherapy within 2 weeks of enrollment onto this study (6 weeks if prior
                  nitrosourea).

               -  Hematopoietic growth factors: At least 14 days must have elapsed after receiving
                  pegfilgrastim and least 7 days must have elapsed since the completion of therapy
                  with a non-pegylated growth factor.

               -  Biologic (anti-neoplastic agent): At least 7 days must have elapsed since
                  completion of therapy with a biologic agent. For agents that have known adverse
                  events occurring beyond 7 days after administration, this period prior to
                  enrollment must be extended beyond the time during which adverse events are known
                  to occur.

               -  Monoclonal antibodies: At least 3 half-lives must have elapsed since prior
                  therapy that included a monoclonal antibody. (See posting of half-lives for
                  commonly used monoclonal antibodies on the DVL homepage;
                  https://members.childrensoncologygroup.org/Disc/devtherapeutics/default.asp.)

               -  Radiotherapy: At least 2 weeks must have elapsed since local palliative XRT
                  (small port); at least 6 weeks must have elapsed since treatment with therapeutic
                  doses of MIBG; at least 3 months must have elapsed if prior craniospinal XRT was
                  received, if more than 50% of the pelvis was irradiated, or if TBI was received;
                  at least 6 weeks must have elapsed if other substantial bone marrow irradiation
                  was given.

          -  Stem cell transplant or rescue without TBI: No evidence of active graft vs. host
             disease and at least 2 months must have elapsed since transplant.

          -  Patients must have a performance status corresponding to Karnofsky or Lansky greater
             than or equal to 50%. Use Karnofsky for patients > 16 years of age and Lansky for
             patients ≤ 16 years of age. 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.

          -  Normal bone marrow and organ function as defined below:

               -  Absolute neutrophil count ≥ 1,000/mcl

               -  Platelets ≥ 100,000/mcl

               -  Total bilirubin ≤ 1.5 x IULN

               -  AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN

               -  Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m^2 for patients with
                  creatinine levels above institutional normal

               -  INR ≤ IULN or PT ≤ IULN

          -  Women of childbearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control, abstinence) prior to study entry and for
             the duration of study participation. Should a woman become pregnant or suspect she is
             pregnant while participating in this study, she must inform her treating physician
             immediately.

          -  Ability to understand and willingness to sign an IRB approved written informed consent
             document (or that of legally authorized representative, if applicable).

        Exclusion Criteria:

          -  A history of other malignancy ≤ 5 years previous with the exception of basal cell or
             squamous cell carcinoma of the skin which were treated with local resection only or
             carcinoma in situ of the cervix.

          -  Currently receiving any other investigational agents.

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to erlotinib, temozolomide, or dacarbazine.

          -  Currently on the following concomitant medications or substances that have the
             potential to affect the activity or pharmacokinetics of the study drug(s). The use of
             the following medications should be discontinued prior to initiation of protocol
             therapy and should be avoided during protocol therapy if reasonable alternatives
             exist.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, renal failure, cardiac arrhythmia,
             interstitial lung disease, hepatic failure / hepatorenal syndrome, GI perforation,
             cerebrovascular event, microangiopathic hemolytic anemia, corneal
             perforation/ulceration, or documented Hepatitis B virus infection.

          -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
             serum or urine pregnancy test within 7 days of study entry.

          -  Known HIV-positivity on combination antiretroviral therapy because of the potential
             for pharmacokinetic interactions with erlotinib or temozolomide. In addition, these
             patients are at increased risk of lethal infections when treated with
             marrow-suppressive therapy. Appropriate studies will be undertaken in patients
             receiving combination antiretroviral therapy when indicated.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate
Time Frame:Completion of treatment (estimated to be 6 months)
Safety Issue:
Description:The overall response rate is the proportion of patients who have complete response or partial response Complete Response (CR): Disappearance of all target lesions, non-target lesions, and normalization of tumor marker level Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

Measure:Time to progression
Time Frame:1 year
Safety Issue:
Description:--Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
Measure:Toxicities of treatment regimen
Time Frame:30 days after completion of treatment (estimated to be 7 months)
Safety Issue:
Description:-The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

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