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

Completed · Phase 1

Conditions studied: Neuroblastoma

In brief

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).

Key facts

Study ID: NCT03107988
Run by: New Approaches to Neuroblastoma Therapy Consortium
People needed: 65
Starts: 2017-09-05
Expected to finish: 2025-01-31
Last updated by the study team: 2025-09-15

Who can join

Age: 1 and older, up to 99. Sex: any. Healthy volunteers: not accepted.

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

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

Where it is running

Children's Hospital Los Angeles — Los Angeles, California, United States
UCSF Helen Diller Family Comprehensive Cancer Center — San Francisco, California, United States
Children Hospital of Colorado — Aurora, Colorado, United States
Children's Healthcare of Atlanta — Atlanta, Georgia, United States
University of Chicago, Comer Children's Hospital — Chicago, Illinois, United States
Childrens Hospital Boston, Dana-Farber Cancer Institute. — Boston, Massachusetts, United States
C.S Mott Children's Hospital — Ann Arbor, Michigan, United States
Children's Hospital of Philadelphia — Philadelphia, Pennsylvania, United States
Cook Children's Healthcare System — Fort Worth, Texas, United States
Children's Hospital and Regional Medical Center - Seattle — Seattle, Washington, United States
Hospital for Sick Children — Toronto, Ontario, Canada
Institut Curie — Paris, Cedex, France
Royal Marsden Hospital — Sutton, Surrey, United Kingdom

Full record on ClinicalTrials.gov

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