Lorlatinib Combinations in Lung Cancer

  • STATUS
    Recruiting
  • participants needed
    96
  • sponsor
    Massachusetts General Hospital
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Updated on 16 February 2024
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anaplastic lymphoma
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cancer refractory
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malabsorption syndrome
binimetinib
metastatic non-small cell lung cancer
kinase inhibitor therapy
ros1 rearrangement
non-small cell lung cancer
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met amplification
alk gene translocation
cns lesion
ros1 gene rearrangement

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

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

Details
Condition Non-Small Cell Lung Cancer, Non-Small Cell Lung Cancer, Pulmonary Disease, Lung Neoplasm, Relapsed Cancer, Anaplastic Lymphoma Kinase Gene Translocation, ROS1 Rearrangement, MET Amplification, Resistant Cancer
Age 18years - 100years
Treatment Binimetinib, Lorlatinib, Crizotinib
Clinical Study IdentifierNCT04292119
SponsorMassachusetts General Hospital
Last Modified on16 February 2024

Eligibility

 Yes No Not Sure

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/L (granulocyte colony-stimulating factor support should not be used within 2 weeks prior to Cycle 1, Day 1)
Platelet count 100,000/L
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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cancer
probe
measurable disease
metastasis
combinations
lung cancer
progressive disease
crizotinib
tubal ligation
cervical cap
lymphoma
immunohistochemistry
metastatic disease
core needle biopsy
major surgery
male sterilization
valproic acid
drug test
stage iv non-small cell lung cancer
tyrosine
traumatic injury
lorlatinib
kinase inhibitor
ros1
discomfort
seizure
ascites
prophylaxis
antiepileptics
levetiracetam
pleural effusion
proto-oncogene tyrosine-protein kinase ros
periodic abstinence
cns metastases
lacosamide
leptomeningeal disease
anaplastic lymphoma
anti-epileptic
malabsorption
cancer refractory
core biopsy
malabsorption syndrome
binimetinib
metastatic non-small cell lung cancer
kinase inhibitor therapy
ros1 rearrangement
non-small cell lung cancer
small cell lung cancer
met amplification
alk gene translocation
cns lesion
ros1 gene rearrangement

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