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

NCT03107988 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: NANT2015-02
• Study Type: interventional
• Target: 65
• Locations: 4 countries
• Sites: 13

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).

Conditions

Neuroblastoma

Outcome Measures

Primary Outcomes (9)

• 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, an average of 10 months

• 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, an average of 10 months

• 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, an average of 10 months

• 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, an average of 10 months

• 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, an average of 10 months

• 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, an average of 10 months

Secondary Outcomes (9)

• Pharmacokinetics A1 and B1-Steady State AUC

  Day 1 through Day 15 (0, 1, 2, 24, 360, 361, 362, 364, 366 hours post-initial dose)

• Pharmacokinetics A2-Steady State AUC

  Day 1 through Day 15 (0, 1, 2, 24, 360, 361, 362, 364, 366 hours post-initial dose)

• Pharmacokinetics B2-Steady State AUC

  Day 1 through Day 15 (0, 1, 2, 24, 360, 361, 362, 364, 366 hours post-initial dose)

• Overall Response A1 and B1

  From Day 1 of protocol therapy through 30 days following end of protocol therapy, an average of 10 months

• Overall Response A2

  From Day 1 of protocol therapy through 30 days following end of protocol therapy, an average of 10 months

Study Arms (13)

Cohort A1 DL1

EXPERIMENTAL

Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 45 mg/m2/dose. Patients must be under 18 years of age at time of enrollment.

Drug: Lorlatinib

Cohort A2 DL 3A

EXPERIMENTAL

Lorlatinib will be given at 100 mg orally once daily continuously for 28 days. Patients must be 18 years of age or older at time of enrollment.

Drug: Lorlatinib

Cohort B2 DL4B

EXPERIMENTAL

Lorlatinib will be given orally once daily continuously for 28 days at 95mg/m2/dose. Lorlatinib should be administered at least one hour prior to conventional chemotherapy (Cyclophosphamide and Topotecan) on days 1-5 of each cycle. Patients must be under 18 years of age at time of enrollment.

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

Cohort A1 DL2

EXPERIMENTAL

Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 60 mg/m2/dose. Patients must be under 18 years of age at time of enrollment.

Drug: Lorlatinib

Cohort A1 DL3

EXPERIMENTAL

Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 75 mg/m2/dose. Patients must be under 18 years of age at time of enrollment.

Drug: Lorlatinib

Cohort A1 DL4

EXPERIMENTAL

Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 95 mg/m2/dose. Patients must be under 18 years of age at time of enrollment.

Drug: Lorlatinib

Cohort A1 DL5

EXPERIMENTAL

Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 115 mg/m2/dose. Patients must be under 18 years of age at time of enrollment.

Drug: Lorlatinib

Cohort A2 DL4A

EXPERIMENTAL

Lorlatinib will be given at 150 mg orally once daily continuously for 28 days. Patients must be 18 years of age or older at time of enrollment.

Drug: Lorlatinib

Cohort B2 DL5B

EXPERIMENTAL

Lorlatinib will be given orally once daily continuously for 28 days at 115mg/m2/dose. Lorlatinib should be administered at least one hour prior to conventional chemotherapy (Cyclophosphamide and Topotecan) on days 1-5 of each cycle. Patients must be under 18 years of age at time of enrollment.

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

Cohort B2 DL3A

EXPERIMENTAL

Lorlatinib will be given orally once daily continuously for 28 days at 100mg/day. Lorlatinib should be administered at least one hour prior to conventional chemotherapy (Cyclophosphamide and Topotecan) on days 1-5 of each cycle. Patients must be 18 years of age or older at time of enrollment.

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

Cohort B2 DL4A

EXPERIMENTAL

Lorlatinib will be given orally once daily continuously for 28 days at 150mg/day. Lorlatinib should be administered at least one hour prior to conventional chemotherapy (Cyclophosphamide and Topotecan) on days 1-5 of each cycle. Patients must be 18 years of age or older at time of enrollment.

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

Cohort B1 DL5

EXPERIMENTAL

Lorlatinib will be given orally once daily continuously for 28 days. The dose level of lorlatinib will be 115 mg/m2/dose. Patients must be under 18 years of age at time of enrollment.

Drug: Lorlatinib

Cohort A2 DL4A Expansion

EXPERIMENTAL

Lorlatinib will be given at 150 mg orally once daily continuously for 28 days. Patients must be 18 years of age or older at time of enrollment.

Drug: Lorlatinib

Interventions

Lorlatinib DRUG

Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.

Also known as: PF06463922

Cohort A1 DL1; Cohort A1 DL2; Cohort A1 DL3; Cohort A1 DL4; Cohort A1 DL5; Cohort A2 DL 3A; Cohort A2 DL4A; Cohort A2 DL4A Expansion; Cohort B1 DL5; Cohort B2 DL3A; Cohort B2 DL4A; Cohort B2 DL4B; Cohort B2 DL5B

Cyclophosphamide DRUG

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

Also known as: Cytoxan

Cohort B2 DL3A; Cohort B2 DL4A; Cohort B2 DL4B; Cohort B2 DL5B

Topotecan DRUG

Topotecan 0.75mg/m2/day will be administered as a 30 minute IV infusion immediately following cyclophosphamide on days 1-5 of each cycle

Also known as: SKF-104864,Hycamtin®

Cohort B2 DL3A; Cohort B2 DL4A; Cohort B2 DL4B; Cohort B2 DL5B

Filgrastim/pegfilgrastim DRUG

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.

Cohort B2 DL3A; Cohort B2 DL4A; Cohort B2 DL4B; Cohort B2 DL5B

Eligibility Criteria

• Age: 1 Year - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• \) 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:
• \. 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.
• \) 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.
• \) 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.
• \) 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):
• For recurrent/progressive or refractory disease, at least one MIBG avid bone site.
• 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.
• 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.
• \) 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.
• \) At least one soft tissue lesion that meets criteria for a TARGET lesion as defined by:
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• 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.
• 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:

You may not qualify if:

• \- 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

Sponsors & Collaborators

• New Approaches to Neuroblastoma Therapy Consortium: lead
• Pfizer: collaborator
• University of Southern California: collaborator
• Solving Kids' Cancer US/EU: collaborator
• Children's Neuroblastoma Cancer Foundation: collaborator
• The Band of Parents: collaborator
• The Evan Foundation: collaborator
• Wade's Army: collaborator
• Ronan Thompson Foundation: collaborator
• The Catherine Elizabeth Blair Memorial Foundation: collaborator
• Cookies for Kids' Cancer: collaborator

Study Sites (13)

Children's Hospital Los Angeles

Los Angeles, California, 90027-0700, United States

Location

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, 94143, United States

Location

Children Hospital of Colorado

Aurora, Colorado, 80045, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

University of Chicago, Comer Children's Hospital

Chicago, Illinois, 60637, United States

Location

Childrens Hospital Boston, Dana-Farber Cancer Institute.

Boston, Massachusetts, 02115, United States

Location

C.S Mott Children's Hospital

Ann Arbor, Michigan, 48109, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104-4318, United States

Location

Cook Children's Healthcare System

Fort Worth, Texas, 76104, United States

Location

Children's Hospital and Regional Medical Center - Seattle

Seattle, Washington, 98105, United States

Location

Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Institut Curie

Paris, Cedex, 05, France

Location

Royal Marsden Hospital

Sutton, Surrey, SM25NG, United Kingdom

Location

Related Publications (2)

• Goldsmith KC, Park JR, Kayser K, Malvar J, Chi YY, Groshen SG, Villablanca JG, Krytska K, Lai LM, Acharya PT, Goodarzian F, Pawel B, Shimada H, Ghazarian S, States L, Marshall L, Chesler L, Granger M, Desai AV, Mody R, Morgenstern DA, Shusterman S, Macy ME, Pinto N, Schleiermacher G, Vo K, Thurm HC, Chen J, Liyanage M, Peltz G, Matthay KK, Berko ER, Maris JM, Marachelian A, Mosse YP. Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results. Nat Med. 2023 May;29(5):1092-1102. doi: 10.1038/s41591-023-02297-5. Epub 2023 Apr 3.

  PMID: 37012551 DERIVED

• 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.

  PMID: 34486544 DERIVED

MeSH Terms

Conditions

Neuroblastoma

Interventions

lorlatinib; Cyclophosphamide; Topotecan; Filgrastim; pegfilgrastim

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Camptothecin; Alkaloids; Heterocyclic Compounds; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: NANT Medical Director
• Organization: New Approaches to Neuroblastoma Therapy

nantops@chla.usc.edu

3233615687

Study Officials

• Yael Mosse, MD

  Children's Hospital of Philadelphia

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 21, 2017
• First Posted: April 11, 2017
• Study Start: September 5, 2017
• Primary Completion: August 22, 2024
• Study Completion: January 31, 2025
• Last Updated: September 15, 2025
• Results First Posted: September 15, 2025

Record last verified: 2025-09

Locations

CA (1); GB (1); FR (1); US (10)