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Study of Lorlatinib (PF-06463922)

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ClinicalTrials.gov Identifier: NCT03107988
Recruitment Status : Recruiting
First Posted : April 11, 2017
Last Update Posted : August 20, 2018
Sponsor:
Collaborators:
Pfizer
University of Southern California
Solving Kids' Cancer US/EU
Children's Neuroblastoma Cancer Foundation
The Band of Parents
The Evan Foundation
Wade's Army
Ronan Thompson Foundation
The Catherine Elizabeth Blair Memorial Foundation
Cookies for Kids' Cancer
Information provided by (Responsible Party):
New Approaches to Neuroblastoma Therapy Consortium

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Neuroblastoma Drug: Lorlatinib Drug: Cyclophosphamide Drug: Topotecan Phase 1

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 1, 2017
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : December 2020


Arm Intervention/treatment
Experimental: Cohort A1 (Dose-finding)
Lorlatinib 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
Drug: Lorlatinib
Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.
Other Name: PF06463922

Experimental: Cohort A2 (Adult and large BSA)
Lorlatinib will be given at the adult recommended phase 2 dose (RP2D) of 100 mg orally once daily continuously for 28 days.
Drug: Lorlatinib
Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.
Other Name: PF06463922

Experimental: Cohort B1 (Expansion)
Lorlatinib 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.
Drug: Lorlatinib
Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.
Other Name: PF06463922

Experimental: Cohort B2 (Combined w/ chemotherapy)
Lorlatinib 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.
Drug: Lorlatinib
Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.
Other Name: PF06463922

Drug: Cyclophosphamide
Cyclophosphamide 250mg/m2/day will be administered as a 30 minute IV infusion on days 1-5 of each cycle
Other Name: Cytoxan

Drug: Topotecan
Topotecan 0.75mg/m2/day will be administered as a 30 minute IV infusion immediately following cyclophosphamide on days 1-5 of each cycle
Other Name: SKF-104864,Hycamtin®




Primary Outcome Measures :
  1. Recommended phase 2 dose of lorlatinib administered orally to children and adolescents [ Time Frame: Approximately 2 years ]
    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.

  2. Toxicities of lorlatinib as a single agent and in combination with topotecan and cyclophosphamide. Will be based on the CTCAE criteria and used to measure the severity of adverse events [ Time Frame: 6 months ]
    Toxicity will be graded using the CTCAE criteria, version 4. The CTCAE provides descriptive terminology and a grading scale for each adverse event listed. A copy of the CTCAE can be downloaded from the CTEP home page (http://ctep.cancer.gov).

  3. Pharmacokinetics: AUC for lorlatinib and metabolite [ Time Frame: Course 1: Day 1, 2, and 15 ]
    Plasma samples will be collected from patients at 3 points on Day 1, at 1 point on Day 2, and at 5 points on day 15

  4. Pharmacokinetics: Clearance for lorlatinib and metabolite [ Time Frame: Course 1: Day 1, 2, and 15 ]
    Plasma samples will be collected from patients at 3 points on Day 1, at 1 point on Day 2, and at 5 points on day 15

  5. Pharmacokinetics: Cmax for lorlatinib and metabolite [ Time Frame: Course 1: Day 1, 2, and 15 ]
    Plasma samples will be collected from patients at 3 points on Day 1, at 1 point on Day 2, and at 5 points on day 15

  6. Pharmacokinetics: Tmax for lorlatinib and metabolite [ Time Frame: Course 1: Day 1, 2, and 15 ]
    Plasma samples will be collected from patients at 3 points on Day 1, at 1 point on Day 2, and at 5 points on day 15

  7. Pharmacokinetics:Terminal half-life for lorlatinib and metabolite [ Time Frame: Course 1: Day 1, 2, and 15 ]
    Plasma samples will be collected from patients at 3 points on Day 1, at 1 point on Day 2, and at 5 points on day 15


Secondary Outcome Measures :
  1. 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. ]
    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.

  2. 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. ]
    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.

  3. 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. ]
    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.

  4. 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. ]
    Bone marrow response is assessed by morphologic and immunohistologic evaluation of bilateral bone marrow aspirates and biopsies



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 90 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03107988


Contacts
Contact: Araz Marachelian, MD 323-361-5687 amarachelian@chla.usc.edu

Locations
United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027-0700
Contact: Araz Marachelian, MD    323-361-5687    amarachelian@chla.usc.edu   
UCSF Helen Diller Family Comprehensive Cancer Center Recruiting
San Francisco, California, United States, 94143
Contact: Katherine K. Matthay, MD    415-476-3831    matthayK@peds.ucsf.edu   
United States, Colorado
Children Hospital of Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Margaret Macy, MD    720-777-8856    Margaret.macy@childrenscolorado.org   
United States, Georgia
Children's Healthcare of Atlanta Recruiting
Atlanta, Georgia, United States, 30322
Contact: Kelly Goldsmith, MD    404-785-0853    kgoldsmith@emory.edu   
United States, Illinois
University of Chicago, Comer Children's Hospital Recruiting
Chicago, Illinois, United States, 60637
Contact: Ami Desai, MD    773-843-3943    adesai12@peds.bsd.uchicago.edu   
United States, Massachusetts
Childrens Hospital Boston, Dana-Farber Cancer Institute. Recruiting
Boston, Massachusetts, United States, 02115
Contact: Suzanne Shusterman, MD    617-632-3725    suzanne_shusterman@dfci.harvard.edu   
United States, Michigan
C.S Mott Children's Hospital Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Rajen Mody, MD       rmody@umich.edu   
United States, North Carolina
University of North Carolina Not yet recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Patrick Thompson, MD       patom@email.unc.edu   
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229-3039
Contact: Brian Weiss, MD    513-636-9866    brian.weiss@chmcc.org   
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104-4318
Contact: Yael Mosse, MD    215-590-0965    mosse@chop.edu   
United States, Texas
Cook Children's Healthcare System Recruiting
Fort Worth, Texas, United States, 76104
Contact: Meaghan Granger, MD    682-885-4007    mgranger@cookchildrens.org   
United States, Washington
Children's Hospital and Regional Medical Center - Seattle Recruiting
Seattle, Washington, United States, 98105
Contact: Navin Pinto, MD    206-987-5783    navin.pinto@seattlechildrens.org   
Canada, Ontario
Hospital for Sick Children Not yet recruiting
Toronto, Ontario, Canada, M5G 1X8
Contact: Meredith Irwin, MD    416-813-7654    meredith.irwin@sickkids.ca   
France
Institut Curie Not yet recruiting
Paris, Cedex, France, 05
Contact: Gudrun Schleiermacher, MD    144324550    gudrun.schleiermacher@curie.fr   
United Kingdom
Royal Marsden Hospital Not yet recruiting
Sutton, Surrey, United Kingdom, SM25NG
Contact: Louis Chelser, MD    2087224204    Louis.Chesler@icr.ac.uk   
Sponsors and Collaborators
New Approaches to Neuroblastoma Therapy Consortium
Pfizer
University of Southern California
Solving Kids' Cancer US/EU
Children's Neuroblastoma Cancer Foundation
The Band of Parents
The Evan Foundation
Wade's Army
Ronan Thompson Foundation
The Catherine Elizabeth Blair Memorial Foundation
Cookies for Kids' Cancer
Investigators
Study Chair: Yael Mosse, MD Children's Hospital of Philadelphia

Responsible Party: New Approaches to Neuroblastoma Therapy Consortium
ClinicalTrials.gov Identifier: NCT03107988     History of Changes
Other Study ID Numbers: NANT2015-02
First Posted: April 11, 2017    Key Record Dates
Last Update Posted: August 20, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Cyclophosphamide
Topotecan
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors