Lorlatinib in Combination With Chemotherapy in Participants With Metastatic Anaplastic Lymphoma Kinase Positive (ALK+) Non-small Cell Lung Cancer (NSCLC) Who Progressed on Single-agent Lorlatinib

NCT05948462 | Withdrawn Phase 2 FDA Drug

• 1 other identifier: LUN 481
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 5

Brief Summary

This clinical trial is an open-label, single arm study evaluating the safest dose of lorlatinib in combination with standard of care chemotherapy in participants with metastatic anaplastic lymphoma kinase positive (ALK+) NSCLC who progressed on prior therapy of lorlatinib alone. The main goals of this study are to:

• Evaluate the safety and tolerability of lorlatinib in combination with standard of care chemotherapy.
• Evaluate how well the combination of lorlatinib and standard of care chemotherapy works to treat metastatic anaplastic lymphoma kinase positive (ALK+) NSCLC.
• Evaluate the pharmacokinetics (PK) of lorlatinib when given in combination with standard of care chemotherapy.

Conditions

Lung Cancer; Non-small Cell Lung Cancer

Keywords

ALK positive; ALK+; Metastatic; Lung; NSCLC; Non-small cell lung cancer; Lorlatinib; Small molecule kinase inhibitor; Pemetrexed; Carboplatin; Cisplatin

Outcome Measures

Primary Outcomes (1)

• Incidence of adverse and serious adverse events of lorlatinib in combination with standard of care platinum-based chemotherapy and pemetrexed as assessed by CTCAE v5.0.

  From Cycle 1 Day 1 to 30 days after treatment discontinuation, up to approximately 1 year. Each cycle is 3 weeks.

Secondary Outcomes (2)

• Pharmacokinetic (PK) analysis: lowest concentration with steady state dosing interval (Css, min) of lorlatinib in combination with standard of care platinum-based chemotherapy and pemetrexed.

  Cycle 1, Day 1; Cycle 2, Day 1; Cycle 4, Day 1 (each cycle is 3 weeks) and at time of treatment discontinuation, up to approximately 1 year.

• Objective Response Rate (ORR) to assess the anti-tumor activity of treatment with lorlatinib in combination with standard of care platinum-based chemotherapy and pemetrexed.

  Up to approximately 26 months

Study Arms (1)

Lorlatinib and Platinum and Pemetrexed

EXPERIMENTAL

Lorlatinib will be administered by mouth daily plus Pemetrexed by IV infusion every 3 weeks until progression or intolerable toxicity. Platinum-based standard of care chemotherapy by IV infusion will also be given every 3 weeks for the first 4 cycles; carboplatin or cisplatin are the platinum agents that may be selected based on physician discretion. One cycle is defined as 3 weeks.

Drug: Lorlatinib; Drug: Cisplatin or Carboplatin; Drug: Pemetrexed

Interventions

Lorlatinib DRUG

Participants will receive assigned dose of daily oral lorlatinib continuously for each cycle. Each cycle is 3 weeks.

Also known as: Lorbrena, Lorviqua

Lorlatinib and Platinum and Pemetrexed

Cisplatin or Carboplatin DRUG

Participants will receive standard of care intravenous Cisplatin or Carboplatin, both chemotherapy medications, on day 1 of each cycle every 3 weeks, for Cycles 1-4. Each cycle is 3 weeks.

Also known as: Platinol (Cisplatin), Paraplatin (Carboplatin)

Lorlatinib and Platinum and Pemetrexed

Pemetrexed DRUG

Participants will receive intravenous Pemetrexed, a chemotherapy medication, on day 1 of each cycle. Each cycle is 3 weeks.

Also known as: Alimta, Pemfexy, Ciambra

Lorlatinib and Platinum and Pemetrexed

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent, according to local guidelines, signed and dated by the participant or by a legal guardian prior to the performance of any study-specific procedures, sampling, or analyses
• At least 18 years-of-age at the time of signature of the informed consent form (ICF)
• Metastatic ALK+ NSCLC
• Clinical and/or radiological progressive disease while receiving lorlatinib monotherapy or within 3 weeks of stopping lorlatinib monotherapy due to clinical and/or radiological progressive disease
• Adequate hematologic function defined as:
• Absolute neutrophil count (ANC) ≥1500/μL
• Hemoglobin (Hb) ≥9 g/dL
• Platelets ≥100,000/μL
• Adequate liver function defined as:
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × the upper limit of normal (ULN)
• Total bilirubin ≤1.5 × ULN (Participants with known Gilbert disease: serum bilirubin level ≤ 3 × ULN)
• Adequate renal function defined as calculated creatinine clearance ≥45 mL/min as calculated by Cockcroft and Gault Formula
• Male or female participants. Male participants with female partners of childbearing potential and female participants of childbearing potential are required to use two forms of acceptable contraception, including one barrier method, during their participation in the study and for 90 days following last dose. Male participants must also refrain from donating sperm during their participation in the study.

You may not qualify if:

• Prior treatment with platinum-based standard of care doublet chemotherapy with pemetrexed
• ECOG Performance Status score ≥3
• Current treatment with any of the following:
• Known strong CYP3A inhibitors (e.g., atazanavir, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, voriconazole, grapefruit juice or grapefruit/grapefruit-related citrus fruits \[e.g., Seville oranges, pomelos\]). The topical use of these medications (if applicable), such as 2% ketoconazole cream, is allowed.
• Known strong CYP3A inducers (e.g., avasimibe, carbamazepine, phenobarbital, phenytoin, rifatutin, rifampin, St. John's Wort)
• CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl including transdermal patch, pimozide, quinidine, sirolimus, tacrolimus) within 12 days prior to the first dose of lorlatinib
• Known P-gp substrates with a narrow therapeutic index (e.g., digoxin)
• Currently receiving treatment with therapeutic doses of warfarin sodium. Low- molecular-weight heparin is allowed.
• Major surgery (excluding placement of vascular access) within 4 weeks of first dose of study drug(s).
• Has any history of ILD (including pulmonary fibrosis or radiation pneumonitis), has clinically significant ILD, or is suspected to have such disease by imaging during screening. If imaging findings are unlikely to indicate a history of pneumonitis, then the Investigator should discuss the considerations with the Study Chair about potential enrollment and record the reasoning in the source documentation.
• Clinically severe pulmonary compromise (based on Investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to:
• any underlying pulmonary disorder (e.g., severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease)
• any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) OR prior pneumonectomy
• Women who are pregnant, nursing, or plan to become pregnant while in the study and for at least 6 months after the last administration of study treatment
• Men who plan to father a child while in the study and for at least 3 months after the last administration of study treatment

Sponsors & Collaborators

• SCRI Development Innovations, LLC: lead
• Pfizer: collaborator

Study Sites (5)

Sarah Cannon Research Institute at HealthONE

Denver, Colorado, 80218, United States

Location

Messino Cancer Center

Asheville, North Carolina, 28806, United States

Location

Tennessee Oncology

Nashville, Tennessee, 37203, United States

Location

Texas Oncology

Dallas, Texas, 75246, United States

Location

Virginia Oncology Associates

Norfolk, Virginia, 23502, United States

Location

MeSH Terms

Conditions

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasm Metastasis

Interventions

lorlatinib; Cisplatin; Carboplatin; Pemetrexed

Condition Hierarchy (Ancestors)

Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Coordination Complexes; Organic Chemicals; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic

Study Officials

• Melissa Johnson, MD

  SCRI Development Innovations, LLC

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 27, 2023
• First Posted: July 17, 2023
• Study Start: November 1, 2023
• Primary Completion: March 1, 2025
• Study Completion: September 1, 2025
• Last Updated: December 13, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)