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

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).

Trial Description

Primary Outcome:

• Recommended phase 2 dose of lorlatinib administered orally to children and adolescents
• Toxicities of lorlatinib as a single agent and in combination with topotecan and cyclophosphamide. Will be based on the CTCAE criteria and used to measure the severity of adverse events
• Pharmacokinetics: AUC for lorlatinib and metabolite
• Pharmacokinetics: Clearance for lorlatinib and metabolite
• Pharmacokinetics: Cmax for lorlatinib and metabolite
• Pharmacokinetics: Tmax for lorlatinib and metabolite
• Pharmacokinetics:Terminal half-life for lorlatinib and metabolite

Secondary Outcome:

• Evaluation of overall response
• Evaluation of soft tissue response
• Evaluation of bone response
• Evaluation of bone marrow response

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.

View this trial on ClinicalTrials.gov