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NANT 2015-02: A Phase 1 Study of Lorlatinib (PF-06463922)

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ClinicalTrials.gov Identifier: NCT03107988
Recruitment Status : Recruiting
First Posted : April 11, 2017
Last Update Posted : May 11, 2022
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 Drug: Filgrastim/pegfilgrastim 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 65 participants
Allocation: Non-Randomized
Intervention Model: Parallel 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 5, 2017
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Neuroblastoma

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®

Drug: Filgrastim/pegfilgrastim

Filgrastim is to be given with each course beginning 24-48 hours following completion of cyclophosphamide and topotecan and continued through post-nadir count recovery with an ANC > 2000/mm^3 at 5mcg/kg/day. Filgrastim must be discontinued at least 24 hours prior to the start of the next course of therapy.

Pegfilgrastim (100mcg/kg; 6mg maximum dose) may be substituted and is given one time at 24-48 hours from completion of cyclophosphamide and topotecan.





Primary Outcome Measures :
  1. MTD/RP2D determination A1 [ Time Frame: All toxicities from enrollment until completion of course 2 (Day 56) ]
    Proportion of patients with course 1 DLT and/or course 2 neuropsychological DLT in cohort A1

  2. MTD/RP2D determination A2 [ Time Frame: All toxicities from enrollment until completion of course 2 (Day 56) ]
    Proportion of patients with course 1 DLT and/or course 2 neuropsychological DLT in cohort A2

  3. MTD/RP2D determination B2 [ Time Frame: All toxicities from enrollment until completion of course 1 (Day 28) ]
    Proportion of patients with course 1 DLT in cohort B2

  4. Describe Non-Hematological Toxicities (A1 and B1) [ Time Frame: All toxicities from enrollment through 30 days following end of protocol therapy ]
    Proportion of patients with any grade 3 or greater non-hematological toxicities on any course in A1 and B1

  5. Describe Hematological Toxicities (A1 and B1) [ Time Frame: All toxicities from enrollment through 30 days following end of protocol therapy ]
    Proportion of patients with any grade 3 or greater hematological toxicities on any course in A1 and B1

  6. Describe Non-Hematological Toxicities (A2) [ Time Frame: All toxicities from enrollment through 30 days following end of protocol therapy ]
    Proportion of patients with any grade 3 or greater non-hematological toxicities in A2

  7. Describe Hematological Toxicities (A2) [ Time Frame: All toxicities from enrollment through 30 days following end of protocol therapy ]
    Proportion of patients with any grade 3 or greater hematological toxicities in A2

  8. Describe Non-Hematological Toxicities (B2) [ Time Frame: All toxicities from enrollment through 30 days following end of protocol therapy ]
    Proportion of patients with any grade 3 or greater non-hematological toxicities in B2

  9. Describe Hematological Toxicities (B2) [ Time Frame: All toxicities from enrollment through 30 days following end of protocol therapy ]
    Proportion of patients with any grade 3 or greater hematological toxicities in B2


Secondary Outcome Measures :
  1. Pharmacokinetics A1 and B1 [ Time Frame: Day 1 through Day 15 ]
    Steady State AUC and Cmax for lorlatinib in patients in cohort A1 and B1

  2. Pharmacokinetics A2 [ Time Frame: Day 1 through Day 15 ]
    Steady State AUC and Cmax for lorlatinib in patients in cohort A2

  3. Pharmacokinetics B2 [ Time Frame: Day 1 through Day 15 ]
    Steady State AUC and Cmax for lorlatinib in patients in cohort B2

  4. Overall Response A1 and B1 [ Time Frame: From Day 1 of protocol therapy through 30 days following end of protocol therapy ]
    Proportion of patients evaluable for response with a best overall response of CR/CR-MD/PR for patients in cohort A1 and B1

  5. Overall Response A2 [ Time Frame: From Day 1 of protocol therapy through 30 days following end of protocol therapy ]
    Proportion of patients evaluable for response with a best overall response of CR/CR-MD/PR for patients in cohort A2

  6. Overall Response B2 [ Time Frame: From Day 1 of protocol therapy through 30 days following end of protocol therapy ]
    Proportion of patients evaluable for response with a best overall response of CR/CR-MD/PR for patients in cohort B2



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year to 99 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

1) 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 2) 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.

3) Patients must have a history of 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.

4) All patients must have at least one of the following

a) Recurrent/progressive disease: after the diagnosis of high risk neuroblastoma at any time prior to enrollment regardless of response to frontline therapy b) No prior history of recurrent/progressive disease since the diagnosis of high risk neuroblastoma b1) Refractory disease- a best overall response of no response/stable disease since diagnosis of high risk neuroblastoma and at least 4 cycles of induction therapy. No prior history of recurrent/progressive disease since the diagnosis of high risk neuroblastoma.

b2) Persistent disease- a best overall response of no partial response since diagnosis of high risk neuroblastoma and at least 4 cycles of induction therapy. No prior history of recurrent/progressive disease since the diagnosis of high risk neuroblastoma.

5) Patients must have at least ONE of the following (lesions may have received prior radiation therapy as long as they meet the other criteria listed below):

  1. For recurrent/progressive or refractory disease, at least one MIBG avid bone site.
  2. For persistent disease, if a patient has 3 or more MIBG avid lesions, then no biopsy is required. If a patients has only 1 or 2 MIBG avid bone lesion sites then biopsy confirmation of neuroblastoma or ganglioneuroblastoma in at least one MIBG avid site present at the time of enrollment is required to be obtained at any time point prior to enrollment.
  3. For MIBG non-avid tumors, patients must have at least one FDG avid site and a biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma at any time prior to enrollment from at least one FDG-avid site.

    6) Any amount of neuroblastoma tumor cells in the bone marrow done at the time of study enrollment based on routine morphology with or without immunocytochemistry in at least one sample from bilateral aspirates and biopsies.

    7) At least one soft tissue lesion that meets criteria for a TARGET lesion as defined by:

  1. SIZE: Lesion can be accurately measured in at least one dimension with a longest diameter ≥ 10 mm, or for lymph nodes ≥ 15 mm on short axis. Lesions meeting size criteria will be considered measurable.
  2. In addition to size, a lesion needs to meet one of the following criteria except for patients with parenchymal CNS lesions which only need to meet size criteria:

    b1) MIBG avid. For patients with recurrent/progressive or refractory disease, no biopsy is required. For patients with persistent disease only: If a patient has only 1 or 2 MIBG avid lesions sites, then biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one MIBG avid site present at time of enrollment is required to be obtained. If a patient has 3 or more MIBG avid lesions, then no biopsy is required.

    b2) MIBG non avid tumors: Patients must have at least one FDG avid site and biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one FDG-PET avid site present at the time of enrollment.

    8) At least one non-target soft tissue lesion that is not measurable, but had a biopsy positive for neuroblastoma and/or ganglioneuroblastoma or is MIBG avid at any time prior to enrollment.

    9) Patients must have a life expectancy of at least 12 weeks and a Lansky (≤16 years) or Karnofsky (>16 years) score of at least 50.

    10) Prior Therapy

    1. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study registration.
    2. Patients must not have received the therapies indicated below after disease evaluation or within the specified time period prior to registration on this study as follows:

    1. Myelosuppressive chemotherapy: must not have received within 2 weeks prior to registration.

    2. Biologic anti-neoplastics- agents not known to be associated with reduced platelet or ANC counts (including retinoids): must not have received within 7 days prior to registration.

    3. Monoclonal antibodies: must have received last dose at least 7 days or 3 half-lives whichever is longer, but no longer than 30 days (with recovery of any associated toxicities), prior to protocol therapy.

    4. Cellular Therapy (e.g. modified T cells, NK cells, dentritic cells etc.): must not have received within 3 weeks and resolution of all toxicities.

    5. Radiation: must not have received small port radiation within 7 days prior to registration.

    6. Hematopoietic Stem Cell Transplant: 7. IVIG 11) All patients must have adequate organ function defined as:

    - Hematological Function:

    1. Absolute Phagocyte count (APC= neutrophils and monocytes): ≥ 1000/µL

    2. Absolute Neutrophil count: ≥750/µL

    3. Absolute Lymphocyte count ≥ 500/µL

    4. Platelet count: ≥ 50,000/µL (A1, A2, and B1); ≥ 75,000/µL (B2), transfusion independent (no platelet transfusions within 1 week)

    5. Hemoglobin ≥ 10 g/dL (may transfuse)

    6. Patients with known bone marrow metastatic disease will be eligible for study as long as they meet hematologic function criteria above.

    - Renal Function: Age-adjusted serum creatinine ≤ to 1.5 x normal for age/gender OR creatinine clearance or GFR greater than or equal to 60 cc/min/1.73m2

    - Liver Function: Total bilirubin ≤ 1.5 x normal for age, AND SGPT (ALT) 135 and SGOT (AST) ≤ 3 x upper limit of normal. Sinusoidal obstruction syndrome (SOS) if present, must be stable or improving clinically

    - Cardiac Function: Normal ejection fraction documented by either echocardiogram or radionuclide MUGA evaluation OR Normal fractional shortening documented by echocardiogram

    - Pulmonary Function: No dyspnea at rest, no oxygen requirement.

    • Neuropsychological Function: Patients must exhibit ≤ grade 1 as defined by CTCAE V4 of nervous system disorders and psychiatric disorders 12) Reproductive Status: All post-menarchal females must have a negative beta-HCG. Males and females of reproductive age and childbearing potential must use effective contraception for the duration of their participation.

      13) Patients with other ongoing serious medical issues must be approved by the study chair prior to registration.

      14) Prior ALK inhibitor treatment- patients must not have been previously treated with lorlatinib. Prior therapy with other ALK inhibitors is allowed.

      15) Concomitant Therapy Restrictions:

      1. Patients may not receive any other anti-cancer agents or radiotherapy while on protocol therapy.
      2. Patient must not be receiving chronic systemic corticosteroids at doses greater than physiologic dosing (inhaled corticosteroids acceptable)
      3. CYP34A inhibitors
      4. CYP34A inducers
      5. CYP34A substrates

    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 with known history of acute or chronic severe psychiatric disorders
    • Patient with current history of suicidal ideation and history of suicide attempt in their lifetime
    • 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
Layout table for location contacts
Contact: Araz Marachelian, MD 323-361-5687 amarachelian@chla.usc.edu

Locations
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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: Kieuhoa Vo, MD    415-476-3831    kieuhoa.vo@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, 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 Recruiting
Toronto, Ontario, Canada, M5G 1X8
Contact: Daniel Morgenstern, MD    416-813-7654    daniel.morgenstern@sickkids.ca   
France
Institut Curie Recruiting
Paris, Cedex, France, 05
Contact: Gudrun Schleiermacher, MD    144324550    gudrun.schleiermacher@curie.fr   
United Kingdom
Royal Marsden Hospital Recruiting
Sutton, Surrey, United Kingdom, SM25NG
Contact: Lynley Marshall, MD    2087224204    lynley.marshall@nhs.net   
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
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Study Chair: Yael Mosse, MD Children's Hospital of Philadelphia
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Responsible Party: New Approaches to Neuroblastoma Therapy Consortium
ClinicalTrials.gov Identifier: NCT03107988    
Other Study ID Numbers: NANT2015-02
First Posted: April 11, 2017    Key Record Dates
Last Update Posted: May 11, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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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