Lorlatinib Combinations in Lung Cancer

NCT04292119 | Unknown Phase 1 DMC FDA Drug

• 1 other identifier: 19-629
• Study Type: interventional
• Target: 96
• Locations: 1 country
• Sites: 2

Brief Summary

This research study is evaluating Lorlatinib in combination with Crizotinib, Binimetinib, or TNO155 as a possible treatment for either anaplastic lymphoma kinase (ALK)-positive lung cancer or ROS1-positive lung cancer.

• This research study involves four study drugs.
• Lorlatinib
• Binimetinib
• Crizotinib
• TNO155

Conditions

Lung Cancer; Anaplastic Lymphoma Kinase Gene Translocation; ROS1 Rearrangement; Relapsed Cancer; MET Amplification; Resistant Cancer; NSCLC

Keywords

Lung Cancer; Anaplastic Lymphoma Kinase Rearrangement; ROS1 Rearrangement; Relapsed Cancer; Resistant Cancer; MET Amplification; NSCLC

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose as assessed by CTCAE v5.0. Phase I.

  The highest dose of the combinations that does not cause unacceptable side effects. The maximum tolerated dose is determined in clinical trials by testing increasing doses in different groups of patients until the highest dose with acceptable side effects is found.

  28 days (binimetinib and crizotinib arm), 21 days (TNO155 arm)

• The objective response rate, including partial and complete responses, as evaluated by RECIST v1.1. Phase II

  Objective response rate (partial and complete responses) will be evaluated according to RECIST v1.1 criteria.

  24 months

Secondary Outcomes (3)

• Number of Participants with Treatment Related Adverse Events as Assessed by CTCAE V5.0

  From first dose to end of study. Time frame is anticipated to be 24 months.

• Progression-Free Survival as assessed by RECIST v1.1 and the Kaplan-Meier Method

  Time from the start of study drug treatment to the date of the first documented progression or death due to disease, likely average of 12 months

• Duration of Response to Treatment as Assessed by RECIST v1.1

  Measured from the time measurement criteria are met for complete or partial response until the first date that recurrent or progressive disease is objectively documented or the date of death due to any cause, likely average of 12 months

Study Arms (3)

Lorlatinib and Crizotinib

EXPERIMENTAL

* The research study procedures include screening for eligibility and study treatment. Study treatment will include evaluations, biopsies, and follow up visits. * Phase 1 (the dose-finding portion of the study) will follow a standard 3+3 design. Enrollment to the different study arms will occur in parallel. * Lorlatinib will be administered orally once daily at a predetermined dose for 28 days * Crizotinib will be administered orally twice daily at a predetermined dose for 28 days * Phase II patients will be treated with Lorlatinib and Crizotinib at a dose recommended based on the phase I study.

Drug: Lorlatinib; Drug: Crizotinib

Lorlatinib and Binimetinib

EXPERIMENTAL

* The research study procedures include screening for eligibility and study treatment. Study treatment will include evaluations, biopsies, and follow up visits. * The phase I part of the study will follow a standard 3+3 design. Enrollment to the different study arms will occur in parallel. * Lorlatinib will be administered orally once daily at a predetermined dose for 28 days * Binimetinib will be administered orally twice daily at a predetermined dose for 28 days. * Phase II patients will be treated with Lorlatinib + Binimetinib at a dose recommended based on the phase I study.

Drug: Lorlatinib; Drug: Binimetinib

Lorlatinib and TNO155

EXPERIMENTAL

* The research study procedures include screening for eligibility and study treatment. Study treatment will include evaluations, biopsies, and follow up visits. * The phase I part of the study will follow a standard 3+3 design. Enrollment to the different study arms will occur in parallel. * Lorlatinib will be administered orally once daily at a predetermined dose for 21 days * TNO155 will be administered orally once daily at a predetermined dose for 14 out of 21 days. * Phase II patients will be treated with Lorlatinib + TNO155 at a dose recommended based on the phase I study.

Drug: Lorlatinib; Drug: TNO155

Interventions

Lorlatinib DRUG

Lorlatinib will be taken orally once daily for 28 days when combined with crizotinib or binimetinib. Lorlatinib will be taken orally once daily for 21 days when combined with TNO155. Crizotinib taken orally twice daily for 28 days.

Also known as: Lorbrena

Lorlatinib and Binimetinib; Lorlatinib and Crizotinib; Lorlatinib and TNO155

Crizotinib DRUG

Crizotinib will be taken orally twice daily for 28 days. Binimetnib taken orally twice daily for 28 days.

Also known as: Xalkori

Lorlatinib and Crizotinib

Binimetinib DRUG

Binimetinib will be taken orally twice daily for 28 days.

Also known as: Mektovi

Lorlatinib and Binimetinib

TNO155 DRUG

TNO155 will be taken orally once daily for 14 days.

Lorlatinib and TNO155

Eligibility Criteria

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

You may qualify if:

• Ability to understand and the willingness to sign a written informed consent document.
• Age ≥ 18 years.
• Histologically or cytologically confirmed diagnosis of metastatic non-small cell lung cancer (Stage IV, AJCC v7.0) that carries an ALK or ROS1 rearrangement (ROS1-positive patients will only be allowed in dose escalation) as determined using a local diagnostic test or a commercial test or by the Food and Drug Administration (FDA)-approved FISH test, using Vysis® ALK Break apart FISH Probe, or the Ventana® immunohistochemistry (IHC) test.
• Disease progression or intolerance to at least one tyrosine kinase inhibitor
• At least one measurable lesion as defined by RECIST version 1.1. Previously irradiated lesions are not measurable unless the lesion has demonstrated clear progression after radiation.
• ECOG performance status ≤ 2
• Life expectancy of greater than 12 weeks
• Patients must be willing to undergo serial biopsies and have disease accessible to pretreatment biopsy. A cell block from a pleural effusion or ascites may be substituted for a core biopsy. In select cases, patients may be allowed to enroll without a pre-treatment biopsy and/or continue treatment without an on-treatment biopsy after speaking with the Overall Principal Investigator if performing the biopsy is technically challenging, poses significant risk to the patient, or may result in significant discomfort. If a pre-treatment biopsy is not performed, archival tissue will be used for correlative studies, specifically plasma-tissue comparisons.
• Able to swallow and retain orally administered medication. Does not have any clinically significant gastrointestinal abnormalities, such as malabsorption syndrome or major resection of the stomach or small bowel that may alter absorption of the medication.
• A minimum washout period of 5 days or 5 half-lives between the last dose of tyrosine kinase inhibitor therapy and the first dose of study treatment is required (whichever is shorter). A shorter washout period may be considered in the event of disease flare, after discussion with the Overall Principal Investigator. No washout is required if the most recent anti-neoplastic therapy is lorlatinib.
• Patients must have recovered from treatment toxicities to ≤ Grade 1 or to their pretreatment levels except for adverse events that in the investigator's judgment do not constitute a safety risk for the patient.
• Patients can either be chemotherapy-naive or have received chemotherapy for locally-advanced or metastatic disease. Acute effects of therapy must have resolved to baseline severity or to CTCAE grade ≤1 except for adverse events that in the investigator's judgment do not constitute a safety risk for the patient.
• Recovery from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment.
• For all women of childbearing potential, a negative pregnancy test must be obtained at the baseline visit before starting study treatment. For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of \< 1% per year, during the treatment period and for at least 90 days after the last dose of study drug.
• Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

You may not qualify if:

• Participants who have had chemotherapy or immunotherapy within 3 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier.
• Participation in other studies involving investigational drug(s) within 1 week prior to study entry and/or during study participation. If the half-life of the investigational drug is known, then a period of 5 half-lives is required (or 1 week whichever is shorter) is required between discontinuing the investigational drug and starting study treatment.
• Radiation therapy (except palliative to relieve bone pain) within 7 days of study entry. Palliative radiation (≤ 10 fractions) must have been completed at least 48 hours prior to study entry. Stereotactic or small field brain irradiation must have been completed at least 48 hours prior to study entry. Whole brain radiation and radiation for leptomeningeal metastasis must have been completed at least 7 days prior to study entry. Acute effects of radiation must have resolved to baseline severity or to CTCAE grade ≤1 except for adverse events that in the investigator's judgment do not constitute a safety risk for the patient.
• Pregnant or lactating women.
• Patients with predisposing characteristics for acute pancreatitis per the investigator's judgment (e.g. uncontrolled hyperglycemia, current symptomatic gallstone disease) in the 2 weeks prior to randomization
• History of hypersensitivity to lorlatinib or any of its excipients. In addition, subjects who are unable to tolerate the 50 mg dose of lorlatinib will not be permitted to enroll unless doses of lorlatinib below the entry level are being investigated (e.g. dose level -1) and they have previously tolerated lorlatinib monotherapy at the dose being investigated.
• History of extensive, disseminated, bilateral or presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis or pulmonary fibrosis. Patients with history of prior radiation pneumonitis are not excluded.
• Serum albumin ≤ 2.5 g/dL
• History of HIV or history of active tuberculosis
• Current use or anticipated need for food or drugs that are known strong CYP3A4 inhibitors, including their administration within 2 weeks prior to the first study treatment (i.e., strong CYP3A4 inhibitors: grapefruit juice or grapefruit/grapefruit related citrus fruits \[e.g., Seville oranges, pomelos\], ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir, troleandomycin, mibefradil, and conivaptan; Moderate CYP3A4 inhibitors: erythromycin, verapamil,atazanavir, delavirdine, fluconazole, darunavir, diltiazem, aprepitant, imatinib, tofisopam,ciprofloxacin, cimetidine).
• Current use or anticipated need for drugs that are known strong CYP3A4 inducers including their administration within 2 weeks prior to the first study treatment (i.e., phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, St. John's Wort).
• Current symptomatic congestive heart failure or history of symptomatic congestive heart failure in the preceding 3 months, defined as NY Heart Association Classification 2- 4
• Binimetinib and TNO155 groups only: Left ventricular ejection fraction \< 50% or institutional lower limit of normal, whichever is lower
• Current diagnosis of symptomatic bradycardia
• Abnormal hematologic and end organ function, defined by the following laboratory results:

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Array BioPharma: collaborator
• Pfizer: collaborator

Study Sites (2)

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

RECRUITING

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

NOT YET RECRUITING

MeSH Terms

Conditions

Lung Neoplasms; Recurrence

Interventions

lorlatinib; Crizotinib; binimetinib

Condition Hierarchy (Ancestors)

Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Aminopyridines; Pyridines

Study Officials

• Ibiayi Dagogo-Jack, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ibiayi Dagogo-Jack, MD

CONTACT

617-724-1134; idagogo-jack@partners.org

Elizabeth Kennedy

CONTACT

617-724-1223; eakennedy@mgh.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 26, 2020
• First Posted: March 2, 2020
• Study Start: May 1, 2020
• Primary Completion: December 1, 2022
• Study Completion: March 1, 2023
• Last Updated: March 10, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Partners Innovations team

Locations

US (2)