NeuroblastomaPhase 1NCT03107988
NANT 2015-02: A Phase 1 Study of Lorlatinib (PF-06463922)
A Phase 1 study testing Lorlatinib, Cyclophosphamide and Topotecan in people with Neuroblastoma, run by New Approaches to Neuroblastoma Therapy Consortium at 13 sites in 4 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 1 year to 99 years
- Conditions the study is for
- Neuroblastoma
- What is being tested?
- Lorlatinib, Cyclophosphamide and Topotecan
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 65 participants
- Where
- 13 sitesin 4 countries
- Study dates
- 5 Sep 2017to 31 Jan 2025
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 99 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
- 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.
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- 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):
- 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.
- 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:
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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:
- 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
- Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study registration.
- 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:
- Patients may not receive any other anti-cancer agents or radiotherapy while on protocol therapy.
- Patient must not be receiving chronic systemic corticosteroids at doses greater than physiologic dosing (inhaled corticosteroids acceptable)
- CYP34A inhibitors
- CYP34A inducers
- CYP34A substrates
Who cannot join
- 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.
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- 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
Trial locations and contacts
13 sites in 4 countries.
13 sites in 4 countries
United States10 sites
C.S Mott Children's Hospital
Ann Arbor, Michigan, 48109
Children's Healthcare of Atlanta
Atlanta, Georgia, 30322
Children Hospital of Colorado
Aurora, Colorado, 80045
Childrens Hospital Boston, Dana-Farber Cancer Institute.
Boston, Massachusetts, 02115
University of Chicago, Comer Children's Hospital
Chicago, Illinois, 60637
Cook Children's Healthcare System
Fort Worth, Texas, 76104
Children's Hospital Los Angeles
Los Angeles, California, 90027-0700
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104-4318
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, 94143
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, 98105
About this study
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
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).
Read the 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.
- Conditions
- Neuroblastoma
- Being tested
- Lorlatinib, Cyclophosphamide, Topotecan, Filgrastim/pegfilgrastim
- Medical subject headings
- Neuroblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LorlatinibDrug
Also called PF06463922
Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets.
CyclophosphamideDrug
Also called Cytoxan
Cyclophosphamide 250mg/m2/day will be administered as a 30 minute IV infusion on days 1-5 of each cycle
TopotecanDrug
Also called SKF-104864,Hycamtin®
Topotecan 0.75mg/m2/day will be administered as a 30 minute IV infusion immediately following cyclophosphamide on days 1-5 of each cycle
Filgrastim/pegfilgrastimDrug
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 group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: Lorlatinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
MTD/RP2D Determination A1
Proportion of patients with course 1 DLT and/or course 2 neuropsychological DLT in cohort A1
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Steady State AUC for lorlatinib in patients in cohort A1 and B1
Measured: Day 1 through Day 15 (0, 1, 2, 24, 360, 361, 362, 364, 366 hours post-initial dose)
Pharmacokinetics A2-Steady State AUC
Steady State AUC for lorlatinib in patients in cohort A2
Measured: Day 1 through Day 15 (0, 1, 2, 24, 360, 361, 362, 364, 366 hours post-initial dose)
Pharmacokinetics B2-Steady State AUC
Steady State AUC for lorlatinib in patients in cohort B2
Measured: Day 1 through Day 15 (0, 1, 2, 24, 360, 361, 362, 364, 366 hours post-initial dose)
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
Measured: From Day 1 of protocol therapy through 30 days following end of protocol therapy, an average of 10 months
Overall Response A2
Proportion of patients evaluable for response with a best overall response of CR/CR-MD/PR for patients in cohort A2
Measured: From Day 1 of protocol therapy through 30 days following end of protocol therapy, an average of 10 months
Overall Response B2
Proportion of patients evaluable for response with a best overall response of CR/CR-MD/PR for patients in cohort B2
Measured: From Day 1 of protocol therapy through 30 days following end of protocol therapy, an average of 10 months
Pharmacokinetics A1 and B1-Cmax
Cmax for lorlatinib in patients in cohort A1 and B1
Measured: Day 15
Pharmacokinetics A2-Cmax
Cmax for lorlatinib in patients in cohort A2
Measured: Day 15
Pharmacokinetics B2-Cmax
Cmax for lorlatinib in patients in cohort B2
Measured: Day 15
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Apr 2017
- Study start5 Sep 2017
- Primary completion22 Aug 2024
- Study completion31 Jan 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for NeuroblastomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 65 participants (actual)
Sponsor and investigators
- Lead sponsor
- New Approaches to Neuroblastoma Therapy Consortium
- Sponsor type
- University, hospital or other
- 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
- Responsible party
- Sponsor
- Investigators
- Yael Mosse, MD, Study chair, Children's Hospital of Philadelphia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03107988
- Sponsor's protocol ID
- NANT2015-02
- Status last verified
- Sep 2025
- First submitted
- 21 Mar 2017
- Last updated
- 15 Sep 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
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.
PubMed 37012551Baranowska-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.
PubMed 34486544
Study at a glance
From the registry record, last updated by the sponsor on 15 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03107988
- Acronym / sponsor ID
- NANT2015-02
- Conditions
- Neuroblastoma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 65 participants (actual)
- Lead sponsor
- New Approaches to Neuroblastoma Therapy ConsortiumUniversity, hospital or other
- 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
- Study start
- 5 Sep 2017 (actual)
- Primary completion
- 22 Aug 2024 (actual)
- Study completion
- 31 Jan 2025 (actual)
- First posted
- 11 Apr 2017 (actual)
- Results
- Posted 15 Sep 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 13
| Arm | Type | Receives |
|---|---|---|
| Cohort A1 DL1 | Experimental | Drug: LorlatinibLorlatinib 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. |
| Cohort A2 DL 3A | Experimental | Drug: LorlatinibLorlatinib 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. |
| Cohort B2 DL4B | Experimental | Drug: Lorlatinib, Drug: Cyclophosphamide, Drug: Topotecan, Drug: Filgrastim/pegfilgrastimLorlatinib 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. |
| Cohort A1 DL2 | Experimental | Drug: LorlatinibLorlatinib 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. |
| Cohort A1 DL3 | Experimental | Drug: LorlatinibLorlatinib 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. |
| Cohort A1 DL4 | Experimental | Drug: LorlatinibLorlatinib 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. |
| Cohort A1 DL5 | Experimental | Drug: LorlatinibLorlatinib 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. |
| Cohort A2 DL4A | Experimental | Drug: LorlatinibLorlatinib 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. |
| Cohort B2 DL5B | Experimental | Drug: Lorlatinib, Drug: Cyclophosphamide, Drug: Topotecan, Drug: Filgrastim/pegfilgrastimLorlatinib 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. |
| Cohort B2 DL3A | Experimental | Drug: Lorlatinib, Drug: Cyclophosphamide, Drug: Topotecan, Drug: Filgrastim/pegfilgrastimLorlatinib 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. |
| Cohort B2 DL4A | Experimental | Drug: Lorlatinib, Drug: Cyclophosphamide, Drug: Topotecan, Drug: Filgrastim/pegfilgrastimLorlatinib 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. |
| Cohort B1 DL5 | Experimental | Drug: LorlatinibLorlatinib 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. |
| Cohort A2 DL4A Expansion | Experimental | Drug: LorlatinibLorlatinib 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. |
Who may qualify
- Ages
- 1 year to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (48 listed)
- 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
- 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.
Key exclusion criteria (10 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LorlatinibAlso: PF06463922Lorlatinib will be given orally once daily continuously in 28-day cycles. Lorlatinib will be provided as 5 mg or 25 mg tablets. | Drug | 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 |
| CyclophosphamideAlso: CytoxanCyclophosphamide 250mg/m2/day will be administered as a 30 minute IV infusion on days 1-5 of each cycle | Drug | Cohort B2 DL3A, Cohort B2 DL4A, Cohort B2 DL4B, Cohort B2 DL5B |
| TopotecanAlso: SKF-104864,Hycamtin®Topotecan 0.75mg/m2/day will be administered as a 30 minute IV infusion immediately following cyclophosphamide on days 1-5 of each cycle | Drug | Cohort B2 DL3A, Cohort B2 DL4A, Cohort B2 DL4B, Cohort B2 DL5B |
| Filgrastim/pegfilgrastimFilgrastim 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. | Drug | Cohort B2 DL3A, Cohort B2 DL4A, Cohort B2 DL4B, Cohort B2 DL5B |
Primary outcome
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, an average of 10 months
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, an average of 10 months
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, an average of 10 months
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, an average of 10 months
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, an average of 10 months
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, an average of 10 months
Proportion of patients with any grade 3 or greater hematological toxicities in B2
9 secondary outcomes
Pharmacokinetics A1 and B1-Steady State AUC
Time frame: Day 1 through Day 15 (0, 1, 2, 24, 360, 361, 362, 364, 366 hours post-initial dose)
Pharmacokinetics A2-Steady State AUC
Time frame: Day 1 through Day 15 (0, 1, 2, 24, 360, 361, 362, 364, 366 hours post-initial dose)
Pharmacokinetics B2-Steady State AUC
Time frame: Day 1 through Day 15 (0, 1, 2, 24, 360, 361, 362, 364, 366 hours post-initial dose)
Overall Response A1 and B1
Time frame: From Day 1 of protocol therapy through 30 days following end of protocol therapy, an average of 10 months
Overall Response A2
Time frame: From Day 1 of protocol therapy through 30 days following end of protocol therapy, an average of 10 months
Overall Response B2
Time frame: From Day 1 of protocol therapy through 30 days following end of protocol therapy, an average of 10 months
Pharmacokinetics A1 and B1-Cmax
Time frame: Day 15
Pharmacokinetics A2-Cmax
Time frame: Day 15
Pharmacokinetics B2-Cmax
Time frame: Day 15
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Sep 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37012551Goldsmith 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.
- Derived from this study: PubMed 34486544Baranowska-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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Yael Mosse, MD study chair
Children's Hospital of Philadelphia
13 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Lorlatinib, Cyclophosphamide and Topotecan in people with Neuroblastoma, run by New Approaches to Neuroblastoma Therapy Consortium at 13 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 48 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in United States, Canada, France, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Sep 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
MTD/RP2D Determination A1 (time frame: All toxicities from enrollment until completion of course 2 (Day 56)). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03107988, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Sep 2025.