Lorlatinib Combinations in Lung Cancer

NCT04292119

Last updated date
Study Location
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, 02114, United States
Contact
617-724-1134

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Lung Cancer, Anaplastic Lymphoma Kinase Gene Translocation, ROS1 Rearrangement, Relapsed Cancer, MET Amplification, Resistant Cancer, NSCLC
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

- 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.

- Examples of contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of <1% per year. Barrier methods must always be supplemented with the use of a spermicide.

- For men: agreement to remain abstinent or use a barrier method of contraception (e.g., condom) during the treatment period and for at least 90 days after the last dose of study drug and agreement to refrain from donating sperm during this same period

- Men with a pregnant partner must agree to remain abstinent or use a condom for the duration of the pregnancy.

- 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.

- Patients with untreated, controlled asymptomatic CNS lesions are permitted to enroll aslong as the CNS was not a site of progressive disease on lorlatinib monotherapy. If the CNS was a site of progressive disease on lorlatinib monotherapy, treatment of CNS lesions is required for enrollment. If CNS lesions are resected, a washout period of at least 28 days is required. This period may be shortened to 14 days with Overall PI approval.

- The use of seizure prophylaxis is allowed as long as patients are taking non-enzyme inducing anti-epileptic drugs (non-EIAED). If patients were previously on EIAEDs and these have been discontinued, they must have been discontinued for at least 7 days prior to treatment start. If patients require an anti-epileptic medication, then a CYP3A4 non-EIAED can be used such as levetiracetam, valproic acid, gabapentin, topiramate or lacosamide.

- Patients requiring steroids for control of CNS metastases must be at a stable or decreasing dose for at least 1 week prior to enrollment

- Patients with asymptomatic leptomeningeal disease are eligible for participation in this trial. However, patients who had progression of leptomeningeal disease on lorlatinib will be required to undergo CNS radiation to meet eligibility.

Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- 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 group 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:


- Absolute neutrophil count ≤ 1500 cells/µL (granulocyte colony-stimulating factor
support should not be used within 2 weeks prior to Cycle 1, Day 1).


- Platelet count ≤100,000/µL


- Hemoglobin ≤ 9.0 g/dL (patients may be transfused above this threshold)


- INR and aPTT ≥ 1.5 x ULN. Patients receiving therapeutic anticoagulation may
exceed these parameters provided they are on a stable dose.


- Serum creatinine ≥1.5x the ULN or an estimated glomerular filtration rate (eGFR)
calculated using the Modification of Diet in Renal Disease (MDRD) equation of <
45 mL/min/1.73 m2


- Serum lipase ≥ 1.5x ULN


- Liver disease characterized by:


- ALT or AST ≥ 3x ULN (or > 5x ULN for patients with concurrent liver metastasis)


- Total bilirubin > 1.5 × ULN; NOTE: Patients with documented Gilbert's syndrome or
hyperbilirubinemia due to nonhepatic cause (e.g., hemolysis, hematoma) may be
enrolled following discussion and agreement with the Overall Principal
Investigator.


- Impaired synthetic function or other conditions of decompensated liver disease,
such ascoagulopathy, hepatic encephalopathy, ascites, and bleeding from
esophageal varices


- Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis


- Binimetinib group only: History of or evidence of retinal pathology on ophthalmologic
examination that is considered a risk factor for neurosensory retinal detachment,
central serous chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular
degeneration.


- Major surgical procedure (including brain surgery) within 28 days prior to Cycle 1,
Day 1 or anticipation of need for a major surgical procedure during the course of the
study.


- Evidence of active malignancy (other than current NSCLC, non-melanoma skin cancer, in
situ cervical cancer, papillary thyroid cancer, localized/stable renal masses,
DCIS/LCIS of the breast, or localized and presumed cured prostate cancer) within the
last 3 years.


- Active inflammatory gastrointestinal disease or previous gastric resection or lap
band.


- Inability or unwillingness to swallow pills


- Concurrent use of other tyrosine kinase inhibitors


- Prior treatment with a MAP-kinase pathway inhibitor (RAS, RAF, ERK, MEK).


- Allergy or hypersensitivity to components of the lorlatinib, binimetinib, or
crizotinibformulations


- Any other diseases, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that would
preclude the use of an investigational drug or that may affect the interpretation of
the results or render the participant at high risk from treatment complications.

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Lung Cancer, Anaplastic Lymphoma Kinase Gene Translocation, ROS1 Rearrangement, Relapsed Cancer, MET Amplification, Resistant Cancer, NSCLCLorlatinib Combinations in Lung Cancer
NCT04292119
  1. Boston, Massachusetts
  2. Boston, Massachusetts
ALL GENDERS
18 Years+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE Lorlatinib Combinations in Lung Cancer
Official Title  ICMJE A Phase IB/II Study of Lorlatinib Combinations in Anaplastic Lymphoma Kinase-Rearranged Lung Cancer
Brief Summary

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

  • This research study involves three study drugs.
  • Lorlatinib
  • Binimetinib
  • Crizotinib
Detailed Description

This is a Phase I/II clinical trial of two investigational combinations for treatment of either anaplastic lymphoma kinase (ALK)-positive or ROS1-positive lung cancer. The two drug combinations being tested are (1) Lorlatinib combined with Crizotinib and (2) Lorlatinib combined with Binimetinib.

  • Lorlatinib is an oral ALK and ROS1 inhibitor. The US Food and Drug Administration (FDA) has approved Lorlatinib for treatment of ALK-positive lung cancer. The FDA has not approved Lorlatinib for treatment of ROS1-positive lung cancer.
  • Crizotinib is an oral ALK and MET inhibitor. The FDA has approved Crizotinib for treatment of ALK-positive lung cancer. Crizotinib is not approved by the FDA for the treatment of MET-positive lung cancer. This study will test crizotinib's ability to block MET signaling. Crizotinib is not approved by the FDA for treatment of ROS1-positive lung cancer.
  • Binimetinib is an oral MEK inhibitor. The FDA has not approved binimetinib for treatment of ALK-positive or ROS1-positive lung cancer but it has been approved for other uses.
  • The FDA has not approved the combination of Lorlatinib with Binimetinib or Crizotinib as a treatment for any disease.

The research study procedures include screening for eligibility and study treatment which will include evaluations and follow up visits.

  • Patients will undergo screening and those who fulfill the eligibility criteria will be assigned to receive either the combination Lorlatinib and Crizotinib or the combination of Lorlatinib and Binimetinib. Patients with ALK-positive or ROS1-positive lung cancer who have extra copies of the MET growth signal (MET amplification) will be assigned to receive the Lorlatinib and Crizotinib combination. All other patients will be randomly assigned to receive one of the combinations.
  • This study consists of 2 parts:

    • Phase I:

      • The investigators are looking to determine whether combining Lorlatinib with either Binimetinib or Crizotinib is well tolerated and to understand how treatment with the two drugs affects cancer cells and impacts growth signals.
      • Not everyone who participates in this research study will receive the same dose of the study drug. The dose given will depend on the number of participants who have been enrolled in the study prior and how well the dose was tolerated.
    • Phase II:

      • The Phase II study will test the safest doses of the combinations (as established in the Phase I study) in a larger group of patients.
      • It is expected that about 96 people will take part in this research study
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Lung Cancer
  • Anaplastic Lymphoma Kinase Gene Translocation
  • ROS1 Rearrangement
  • Relapsed Cancer
  • MET Amplification
  • Resistant Cancer
  • NSCLC
Intervention  ICMJE
  • Drug: Lorlatinib

    Lorlatinib will be taken orally once daily for 28 days.

    Crizotinib taken orally twice daily for 28 days.

    Other Name: Lorbrena
  • Drug: Crizotinib

    Crizotinib will be taken orally twice daily for 28 days.

    Binimetnib taken orally twice daily for 28 days.

    Other Name: Xalkori
  • Drug: Binimetinib
    Binimetinib will be taken orally twice daily for 28 days.
    Other Name: Mektovi
Study Arms  ICMJE
  • Experimental: Lorlatinib and Crizotinib
    • 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 two 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.
    Interventions:
    • Drug: Lorlatinib
    • Drug: Crizotinib
  • Experimental: Lorlatinib and Binimetinib
    • 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 two 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.
    Interventions:
    • Drug: Lorlatinib
    • Drug: Binimetinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 28, 2020)
96
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 1, 2023
Estimated Primary Completion Date December 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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.
    • Examples of contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of <1% per year. Barrier methods must always be supplemented with the use of a spermicide.
  • For men: agreement to remain abstinent or use a barrier method of contraception (e.g., condom) during the treatment period and for at least 90 days after the last dose of study drug and agreement to refrain from donating sperm during this same period
  • Men with a pregnant partner must agree to remain abstinent or use a condom for the duration of the pregnancy.
  • 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.
  • Patients with untreated, controlled asymptomatic CNS lesions are permitted to enroll aslong as the CNS was not a site of progressive disease on lorlatinib monotherapy. If the CNS was a site of progressive disease on lorlatinib monotherapy, treatment of CNS lesions is required for enrollment. If CNS lesions are resected, a washout period of at least 28 days is required. This period may be shortened to 14 days with Overall PI approval.
  • The use of seizure prophylaxis is allowed as long as patients are taking non-enzyme inducing anti-epileptic drugs (non-EIAED). If patients were previously on EIAEDs and these have been discontinued, they must have been discontinued for at least 7 days prior to treatment start. If patients require an anti-epileptic medication, then a CYP3A4 non-EIAED can be used such as levetiracetam, valproic acid, gabapentin, topiramate or lacosamide.
  • Patients requiring steroids for control of CNS metastases must be at a stable or decreasing dose for at least 1 week prior to enrollment
  • Patients with asymptomatic leptomeningeal disease are eligible for participation in this trial. However, patients who had progression of leptomeningeal disease on lorlatinib will be required to undergo CNS radiation to meet eligibility.

Exclusion Criteria:

  • 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 group 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:

    • Absolute neutrophil count ? 1500 cells/µL (granulocyte colony-stimulating factor support should not be used within 2 weeks prior to Cycle 1, Day 1).
    • Platelet count ?100,000/µL
    • Hemoglobin ? 9.0 g/dL (patients may be transfused above this threshold)
    • INR and aPTT ? 1.5 x ULN. Patients receiving therapeutic anticoagulation may exceed these parameters provided they are on a stable dose.
    • Serum creatinine ?1.5x the ULN or an estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease (MDRD) equation of < 45 mL/min/1.73 m2
    • Serum lipase ? 1.5x ULN
  • Liver disease characterized by:

    • ALT or AST ? 3x ULN (or > 5x ULN for patients with concurrent liver metastasis)
    • Total bilirubin > 1.5 × ULN; NOTE: Patients with documented Gilbert's syndrome or hyperbilirubinemia due to nonhepatic cause (e.g., hemolysis, hematoma) may be enrolled following discussion and agreement with the Overall Principal Investigator.
    • Impaired synthetic function or other conditions of decompensated liver disease, such ascoagulopathy, hepatic encephalopathy, ascites, and bleeding from esophageal varices
    • Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis
  • Binimetinib group only: History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, central serous chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration.
  • Major surgical procedure (including brain surgery) within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study.
  • Evidence of active malignancy (other than current NSCLC, non-melanoma skin cancer, in situ cervical cancer, papillary thyroid cancer, localized/stable renal masses, DCIS/LCIS of the breast, or localized and presumed cured prostate cancer) within the last 3 years.
  • Active inflammatory gastrointestinal disease or previous gastric resection or lap band.
  • Inability or unwillingness to swallow pills
  • Concurrent use of other tyrosine kinase inhibitors
  • Prior treatment with a MAP-kinase pathway inhibitor (RAS, RAF, ERK, MEK).
  • Allergy or hypersensitivity to components of the lorlatinib, binimetinib, or crizotinibformulations
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that would preclude the use of an investigational drug or that may affect the interpretation of the results or render the participant at high risk from treatment complications.
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ibiayi Dagogo-Jack, MD617-724-1134[email protected]
Contact: Elizabeth Kennedy617-724-1223[email protected]
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04292119
Other Study ID Numbers  ICMJE 19-629
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD:Yes
Plan Description:The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
Supporting Materials:Study Protocol
Supporting Materials:Statistical Analysis Plan (SAP)
Supporting Materials:Informed Consent Form (ICF)
Time Frame:Data can be shared no earlier than 1 year following the date of publication
Access Criteria:Contact the Partners Innovations team
URL:http://www.partners.org/innovation
Responsible Party Ibiayi Dagogo-Jack, M.D., Massachusetts General Hospital
Study Sponsor  ICMJE Massachusetts General Hospital
Collaborators  ICMJE
  • Array BioPharma
  • Pfizer
Investigators  ICMJE
Principal Investigator:Ibiayi Dagogo-Jack, MDMassachusetts General Hospital
PRS Account Massachusetts General Hospital
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP