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

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.

• 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®

• 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

Inclusion Criteria:

• 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 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.
• Patients must have 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.
• Patients must have at least ONE of the following: 1) Recurrent/progressive disease at any time prior to study enrollment, 2) Refractory disease, 3) Persistent disease
• Patients must have at least ONE of the following: 1) Bone disease, 2) Any amount of neuroblastoma tumor cells in the bone marrow, 3) At least one soft tissue lesion that meets criteria for a TARGET lesion, 4) At least one non-target soft tissue lesion that is not measurable, but had a biopsy positive for neuroblastoma and/or ganglioneuroblastoma at any time prior to enrollment or is MIBG avid
• Patients must have a Lansky (?16 years) or Karnofsky (> 16 years) score of at least 50
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
• Patients must not have been previously treated with lorlatinib.
• Patients must not have received any of the specified therapies as stated in the protocol in the time period prior to registration
• Patients must not be receiving any other anti-cancer agents or radiotherapy at the time of study entry or while on study.
• Patients must not be receiving other investigational medications (covered under another IND) within 30 days of study entry or while on study.
• Patients must not be receiving chronic systemic corticosteroids at doses greater than physiologic dosing (inhaled corticosteroids acceptable).
• Patient must meet the organ function and system function requirements as stated in the protocol

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 declines participation in NANT 2004-05, the NANT Biology Study

• 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