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

• ClinicalTrials.gov Identifier: NCT03107988
• Recruitment Status: Active, not recruiting
• First Posted: April 11, 2017
• Last Update Posted: February 9, 2024
• Sponsor: New Approaches to Neuroblastoma Therapy Consortium
• 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

Tracking Information

• First Submitted Date: March 21, 2017
• First Posted Date: April 11, 2017
• Last Update Posted Date: February 9, 2024
• Actual Study Start Date: September 5, 2017
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 5, 2022)

• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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

Original Primary Outcome Measures (submitted: April 4, 2017)

• 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.
• 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).
• 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
• 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
• 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
• 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
• 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

Current Secondary Outcome Measures (submitted: May 5, 2022)

• 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
• Pharmacokinetics A2 [ Time Frame: Day 1 through Day 15 ]
  Steady State AUC and Cmax for lorlatinib in patients in cohort A2
• Pharmacokinetics B2 [ Time Frame: Day 1 through Day 15 ]
  Steady State AUC and Cmax for lorlatinib in patients in cohort B2
• 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
• 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
• 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

Original Secondary Outcome Measures (submitted: April 4, 2017)

• 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.
• 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.
• 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.
• 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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: NANT 2015-02: A Phase 1 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
• 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).

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
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Neuroblastoma

Intervention

• 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.

Study Arms

• 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
  Intervention: Drug: Lorlatinib
• 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.
  Intervention: Drug: Lorlatinib
• 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.
  Intervention: Drug: Lorlatinib
• 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.
  Interventions:

  • Drug: Lorlatinib
  • Drug: Cyclophosphamide
  • Drug: Topotecan
  • Drug: Filgrastim/pegfilgrastim

• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: May 5, 2022): 65
• Original Estimated Enrollment (submitted: April 4, 2017): 40
• Estimated Study Completion Date: December 2025
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Year to 99 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, France, United Kingdom, United States

Administrative Information

• NCT Number: NCT03107988
• Other Study ID Numbers: NANT2015-02
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: New Approaches to Neuroblastoma Therapy Consortium
• Original Responsible Party: Same as current
• Current Study Sponsor: New Approaches to Neuroblastoma Therapy Consortium
• Original Study Sponsor: Same as current

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

Investigators

• Study Chair: Yael Mosse, MD; Children's Hospital of Philadelphia

• PRS Account: New Approaches to Neuroblastoma Therapy Consortium
• Verification Date: February 2024