Clinical Trials /

Study of Lorlatinib (PF-06463922)

NCT03107988

Description:

Lorlatinib is a novel inhibitor across ALK variants, including those resistant to crizotinib. In this first pediatric phase 1 trial of lorlatinib, the drug will be utilized as a single agent and in combination with chemotherapy in patients with relapsed/refractory neuroblastoma. The dose escalation phase of this study (Cohort A1) uses a traditional Phase I 3+3 design. Once a recommended phase 2 pediatric dose is identified, an expansion cohort of 6 patients (Cohort B1), within which ALKi naïve patients will be prioritized, will be initiated. Parallel cohorts will be initiated in adults or patients with large BSA (Cohort A2) and in combination with chemotherapy upon establishing RP2D (Cohort B2).

Related Conditions:
  • Neuroblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of Lorlatinib (PF-06463922)
  • Official Title: Phase 1 Study of Lorlatinib (PF-06463922), an Oral Small Molecule Inhibitor of ALK/ROS1, for Patients With ALK-Driven Relapsed or Refractory Neuroblastoma

Clinical Trial IDs

  • ORG STUDY ID: N2015-02
  • NCT ID: NCT03107988

Conditions

  • Neuroblastoma

Interventions

DrugSynonymsArms
LorlatinibPF06463922Cohort A1 (Dose-finding)
CyclophosphamideCytoxanCohort B2 (Combined w/ chemotherapy)
TopotecanSKF-104864,Hycamtin®Cohort B2 (Combined w/ chemotherapy)

Purpose

Lorlatinib is a novel inhibitor across ALK variants, including those resistant to crizotinib. In this first pediatric phase 1 trial of lorlatinib, the drug will be utilized as a single agent and in combination with chemotherapy in patients with relapsed/refractory neuroblastoma. The dose escalation phase of this study (Cohort A1) uses a traditional Phase I 3+3 design. Once a recommended phase 2 pediatric dose is identified, an expansion cohort of 6 patients (Cohort B1), within which ALKi naïve patients will be prioritized, will be initiated. Parallel cohorts will be initiated in adults or patients with large BSA (Cohort A2) and in combination with chemotherapy upon establishing RP2D (Cohort B2).

Detailed Description

      Lorlatinib is a novel inhibitor across ALK variants, including those resistant to
      crizotinib. An adult phase 1 study established an RP2D of 100mg QD for lorlatinib. In this
      first pediatric phase 1 trial of lorlatinib, the drug will be utilized as a single agent and
      in combination with chemotherapy in patients with relapsed/refractory neuroblastoma. The
      dose escalation phase of this study (Cohort A1) uses a traditional Phase I 3+3 design. Once
      a recommended phase 2 pediatric dose is identified, an expansion cohort of 6 patients
      (Cohort B1), within which ALKi naïve patients will be prioritized, will be initiated.
      Parallel cohorts will be initiated in adults or patients with large BSA (Cohort A2) and in
      combination with chemotherapy upon establishing RP2D (Cohort B2).

      Lorlatinib will be administered orally via tablets or via oral dispersion if patient is
      unable to swallow tablets whole

      All patients will participate in mandatory pharmacokinetic testing.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort A1 (Dose-finding)ExperimentalLorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be assigned at the time of study registration. The starting dose for cohort A1 is 45 mg/m2/dose
  • Lorlatinib
Cohort A2 (Adult and large BSA)ExperimentalLorlatinib will be given at the adult recommended phase 2 dose (RP2D) of 100 mg orally once daily continuously for 28 days.
  • Lorlatinib
Cohort B1 (Expansion)ExperimentalLorlatinib will be given orally once daily continuously for 28 days at the RP2D defined by cohort A1. This cohort will not begin enrollment until the recommended phase 2 dose is established from the dose escalation cohort A1.
  • Lorlatinib
Cohort B2 (Combined w/ chemotherapy)ExperimentalLorlatinib will be given orally once daily continuously for 28 days, at the RP2D defined by cohort A1. Lorlatinib should be administered at least one hour prior to conventional chemotherapy (Cyclophosphamide and Topotecan) on days 1-5 of each cycle.
  • Lorlatinib
  • Cyclophosphamide
  • Topotecan

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a diagnosis of neuroblastoma either by histologic verification of
             neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased
             urinary catecholamines

          -  Patients are required to have an activating ALK aberration in their tumor detected by
             certified assay (i.e. CLIA in the US.) prior to registration. The report from this
             test is required to be submitted for eligibility. Patients with at least one of the
             following genetic features in their tumor will be considered to have an activating
             ALK aberration:

               1. An ALK activating mutation;

               2. ALK amplification (> 10 signals of the ALK gene);

               3. Presence of any ALK fusion protein that arises from a chromosomal translocation.

          -  Patients must have high risk neuroblastoma according to COG risk classification at
             the time of study registration. Patients who were initially considered low or
             intermediate risk, but then reclassified as high risk are also eligible.

          -  Patients must have at least ONE of the following: 1) Recurrent/progressive disease at
             any time prior to study enrollment, 2) Refractory disease, 3) Persistent disease

          -  Patients must have at least ONE of the following: 1) Bone disease, 2) Any amount of
             neuroblastoma tumor cells in the bone marrow, 3) At least one soft tissue lesion that
             meets criteria for a TARGET lesion, 4) At least one non-target soft tissue lesion
             that is not measurable, but had a biopsy positive for neuroblastoma and/or
             ganglioneuroblastoma at any time prior to enrollment or is MIBG avid

          -  Patients must have a Lansky (≤16 years) or Karnofsky (> 16 years) score of at least
             50

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

          -  Patients must not have been previously treated with lorlatinib.

          -  Patients must not have received any of the specified therapies as stated in the
             protocol in the time period prior to registration

          -  Patients must not be receiving any other anti-cancer agents or radiotherapy at the
             time of study entry or while on study.

          -  Patients must not be receiving other investigational medications (covered under
             another IND) within 30 days of study entry or while on study.

          -  Patients must not be receiving chronic systemic corticosteroids at doses greater than
             physiologic dosing (inhaled corticosteroids acceptable).

          -  Patient must meet the organ function and system function requirements as stated in
             the protocol

        Exclusion Criteria:

          -  Pregnancy, breast feeding, or unwillingness to use effective contraception during the
             study.

          -  Patients who, in the opinion of the investigator, may not be able to comply with the
             safety monitoring requirements of the study.

          -  Patients with disease of any major organ system that would compromise their ability
             to withstand therapy.

          -  Patients who have received prior allogeneic stem cell transplant

          -  Patients who are on hemodialysis.

          -  Patients with an active or uncontrolled infection.

          -  Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or
             hepatitis C.

          -  Patient declines participation in NANT 2004-05, the NANT Biology Study
      
Maximum Eligible Age:90 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose of lorlatinib administered orally to children and adolescents
Time Frame:Approximately 2 years
Safety Issue:
Description:By dose level (Dose Escalation of lorlatinib Only; The entry dose of lorlatinib at 45 mg/m2 /dose is equivalent to 75% of the adult RP2D). Two to six evaluable patients will be entered at each of the three dose levels for determination of the maximum tolerated dose.

Secondary Outcome Measures

Measure:Evaluation of overall response
Time Frame:Overall response is assessed at 8, 16, 24, 40, and 56 weeks from start of therapy, and then every 16 weeks, and at end of protocol therapy; an average of 24 weeks.
Safety Issue:
Description:Overall response is the measure that will be used to assess anti-tumor activity, and is determined by integration of the soft tissue response, bone response, and bone marrow response according to the NANT Response Criteria, Version 2.0 definitions. Responders are defined as patients with an overall response of Complete Response, Complete Response-Minimal Disease, or Partial Response.
Measure:Evaluation of soft tissue response
Time Frame:Soft tissue response is assessed at 8, 16, 24, 40, and 56 weeks from start of therapy, and then every 16 weeks, and at end of protocol therapy; an average of 24 weeks.
Safety Issue:
Description:Soft tissue response is assessed by CT/MRI scans using RECIST criteria to define measurable lesions with the addition of MIBG and/or FDG-PET (only for MIBG non-avid tumors) avidity and/or biopsy to define target lesions for response.
Measure:Evaluation of bone response
Time Frame:Bone response is assessed at 8, 16, 24, 40, and 56 weeks from start of therapy, and then every 16 weeks, and at end of protocol therapy; an average of 24 weeks.
Safety Issue:
Description:Bone response is assessed by MIBG scans for MIBG avid tumors, and by FDG-PET scans for MIBG non-avid tumors, using sectors 1-9 of the Curie scoring to determine the relative score at each response timepoint.
Measure:Evaluation of bone marrow response
Time Frame:Bone marrow response is assessed at 8, 16, 24, 40, and 56 weeks from start of therapy, and then every 16 weeks, and at end of protocol therapy; an average of 24 weeks.
Safety Issue:
Description:Bone marrow response is assessed by morphologic and immunohistologic evaluation of bilateral bone marrow aspirates and biopsies

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:New Approaches to Neuroblastoma Therapy Consortium

Last Updated

April 4, 2017