Clinical trial NCT03107988: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Neuroblastoma
Lead sponsor: New Approaches to Neuroblastoma Therapy Consortium
Sponsor class: OTHER
Collaborators: name: Pfizer
name: University of Southern California
name: Solving Kids' Cancer US/EU
name: Children's Neuroblastoma Cancer Foundation
name: The Band of Parents
name: The Evan Foundation
name: Wade's Army
name: Ronan Thompson Foundation
name: The Catherine Elizabeth Blair Memorial Foundation
name: Cookies for Kids' Cancer
First posted: 2017-04-11
Enrollment: 65
Sex: ALL
Minimum age (years): 1
Maximum age (years): 99
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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:

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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

Primary outcomes:
measure: MTD/RP2D determination A1
timeFrame: All toxicities from enrollment until completion of course 2 (Day 56)
measure: MTD/RP2D determination A2
timeFrame: All toxicities from enrollment until completion of course 2 (Day 56)
measure: MTD/RP2D determination B2
timeFrame: All toxicities from enrollment until completion of course 1 (Day 28)
measure: Describe Non-Hematological Toxicities (A1 and B1)
timeFrame: All toxicities from enrollment through 30 days following end of protocol therapy
measure: Describe Hematological Toxicities (A1 and B1)
timeFrame: All toxicities from enrollment through 30 days following end of protocol therapy
measure: Describe Non-Hematological Toxicities (A2)
timeFrame: All toxicities from enrollment through 30 days following end of protocol therapy
measure: Describe Hematological Toxicities (A2)
timeFrame: All toxicities from enrollment through 30 days following end of protocol therapy
measure: Describe Non-Hematological Toxicities (B2)
timeFrame: All toxicities from enrollment through 30 days following end of protocol therapy
measure: Describe Hematological Toxicities (B2)
timeFrame: All toxicities from enrollment through 30 days following end of protocol therapy
Secondary outcomes:
measure: Pharmacokinetics A1 and B1
timeFrame: Day 1 through Day 15
measure: Pharmacokinetics A2
timeFrame: Day 1 through Day 15
measure: Pharmacokinetics B2
timeFrame: Day 1 through Day 15
measure: Overall Response A1 and B1
timeFrame: From Day 1 of protocol therapy through 30 days following end of protocol therapy
measure: Overall Response A2
timeFrame: From Day 1 of protocol therapy through 30 days following end of protocol therapy
measure: Overall Response B2
timeFrame: From Day 1 of protocol therapy through 30 days following end of protocol therapy
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: Children Hospital of Colorado
state: Colorado
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Chicago
country: United States
facility: University of Chicago, Comer Children's Hospital
state: Illinois
city: Boston
country: United States
facility: Childrens Hospital Boston, Dana-Farber Cancer Institute.
state: Massachusetts
city: Ann Arbor
country: United States
facility: C.S Mott Children's Hospital
state: Michigan
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Fort Worth
country: United States
facility: Cook Children's Healthcare System
state: Texas
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Paris
country: France
facility: Institut Curie
state: Cedex
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital
state: Surrey
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Yael Mosse, MD
role: STUDY_CHAIR
References:
citation: 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.