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

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Neuroblastoma
• Intervention / Treatment: Drug: Lorlatinib; Drug: Cyclophosphamide; Drug: Topotecan; Drug: Filgrastim/pegfilgrastim

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
• Enrollment (Actual): 65
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Araz Marachelian, MD; Phone Number: 323-361-5687; Email: amarachelian@chla.usc.edu

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
• France
  • Cedex
    • Paris, Cedex, France, 05
      • Institut Curie
• United Kingdom
  • Surrey
    • Sutton, Surrey, United Kingdom, SM25NG
      • Royal Marsden Hospital
• United States
  • California
    • Los Angeles, California, United States, 90027-0700
      • Children's Hospital Los Angeles
    • San Francisco, California, United States, 94143
      • UCSF Helen Diller Family Comprehensive Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children Hospital of Colorado
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago, Comer Children's Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Childrens Hospital Boston, Dana-Farber Cancer Institute.
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C.S Mott Children'S Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-4318
      • Children's Hospital of Philadelphia
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Healthcare System
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 97 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: 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 Names: PF06463922; Drug: Cyclophosphamide; Cyclophosphamide 250mg/m2/day will be administered as a 30 minute IV infusion on days 1-5 of each cycle; Other Names: 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 Names: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MTD/RP2D determination A1	Proportion of patients with course 1 DLT and/or course 2 neuropsychological DLT in cohort A1	All toxicities from enrollment until completion of course 2 (Day 56)
MTD/RP2D determination A2	Proportion of patients with course 1 DLT and/or course 2 neuropsychological DLT in cohort A2	All toxicities from enrollment until completion of course 2 (Day 56)
MTD/RP2D determination B2	Proportion of patients with course 1 DLT in cohort B2	All toxicities from enrollment until completion of course 1 (Day 28)
Describe Non-Hematological Toxicities (A1 and B1)	Proportion of patients with any grade 3 or greater non-hematological toxicities on any course in A1 and B1	All toxicities from enrollment through 30 days following end of protocol therapy
Describe Hematological Toxicities (A1 and B1)	Proportion of patients with any grade 3 or greater hematological toxicities on any course in A1 and B1	All toxicities from enrollment through 30 days following end of protocol therapy
Describe Non-Hematological Toxicities (A2)	Proportion of patients with any grade 3 or greater non-hematological toxicities in A2	All toxicities from enrollment through 30 days following end of protocol therapy
Describe Hematological Toxicities (A2)	Proportion of patients with any grade 3 or greater hematological toxicities in A2	All toxicities from enrollment through 30 days following end of protocol therapy
Describe Non-Hematological Toxicities (B2)	Proportion of patients with any grade 3 or greater non-hematological toxicities in B2	All toxicities from enrollment through 30 days following end of protocol therapy
Describe Hematological Toxicities (B2)	Proportion of patients with any grade 3 or greater hematological toxicities in B2	All toxicities from enrollment through 30 days following end of protocol therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics A1 and B1	Steady State AUC and Cmax for lorlatinib in patients in cohort A1 and B1	Day 1 through Day 15
Pharmacokinetics A2	Steady State AUC and Cmax for lorlatinib in patients in cohort A2	Day 1 through Day 15
Pharmacokinetics B2	Steady State AUC and Cmax for lorlatinib in patients in cohort B2	Day 1 through Day 15
Overall Response A1 and B1	Proportion of patients evaluable for response with a best overall response of CR/CR-MD/PR for patients in cohort A1 and B1	From Day 1 of protocol therapy through 30 days following end of protocol therapy
Overall Response A2	Proportion of patients evaluable for response with a best overall response of CR/CR-MD/PR for patients in cohort A2	From Day 1 of protocol therapy through 30 days following end of protocol therapy
Overall Response B2	Proportion of patients evaluable for response with a best overall response of CR/CR-MD/PR for patients in cohort B2	From Day 1 of protocol therapy through 30 days following end of protocol therapy

Collaborators and Investigators

• Sponsor: New Approaches to Neuroblastoma Therapy Consortium
• Collaborators: Pfizer; University of Southern California; Cookies for Kids' Cancer; The Evan Foundation; Solving Kids' Cancer US/EU; The Band of Parents; Children's Neuroblastoma Cancer Foundation; Wade's Army; Ronan Thompson Foundation; The Catherine Elizabeth Blair Memorial Foundation
• Investigators: Study Chair: Yael Mosse, MD, Children's Hospital of Philadelphia

Publications and helpful links

General Publications

• Baranowska-Kortylewicz J, Kortylewicz ZP, McIntyre EM, Sharp JG, Coulter DW. Multifarious Functions of Butyrylcholinesterase in Neuroblastoma: Impact of BCHE Deletion on the Neuroblastoma Growth In Vitro and In Vivo. J Pediatr Hematol Oncol. 2022 Aug 1;44(6):293-304. doi: 10.1097/MPH.0000000000002285. Epub 2021 Sep 6.

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2017
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: March 21, 2017
• First Submitted That Met QC Criteria: April 4, 2017
• First Posted (Actual): April 11, 2017

Study Record Updates

• Last Update Posted (Estimated): February 9, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Cyclophosphamide; Topotecan
• Other Study ID Numbers: NANT2015-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No