Clinical Trials /

Lorlatinib Combinations in Lung Cancer

NCT04292119

Description:

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

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Lorlatinib Combinations in Lung Cancer
  • Official Title: A Phase IB/II Study of Lorlatinib Combinations in Anaplastic Lymphoma Kinase-Rearranged Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: 19-629
  • NCT ID: NCT04292119

Conditions

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

Interventions

DrugSynonymsArms
LorlatinibLorbrenaLorlatinib and Binimetinib
CrizotinibXalkoriLorlatinib and Crizotinib
BinimetinibMektoviLorlatinib and Binimetinib

Purpose

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
    

Trial Arms

NameTypeDescriptionInterventions
Lorlatinib and CrizotinibExperimentalThe 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.
  • Lorlatinib
  • Crizotinib
Lorlatinib and BinimetinibExperimentalThe 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.
  • Lorlatinib
  • Binimetinib

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose as assessed by CTCAE v5.0. Phase I.
Time Frame:28 days
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Number of Participants with Treatment Related Adverse Events as Assessed by CTCAE V5.0
Time Frame:From first dose to end of study. Time frame is anticipated to be 24 months.
Safety Issue:
Description:Number of patients with treatment-related side effects, according to CTCAE v5.0
Measure:Progression-Free Survival as assessed by RECIST v1.1 and the Kaplan-Meier Method
Time Frame: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
Safety Issue:
Description:PFS will defined as the time from the start of treatment to the date of the first documented progression or death due to disease. The distribution of PFS will be estimated using the Kaplan-Meier method.
Measure:Duration of Response to Treatment as Assessed by RECIST v1.1
Time Frame: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
Safety Issue:
Description:Duration of response to treatment is measured from the time that measurement criteria (RECIST v1.1) are met for complete response or partial response (whichever is recorded first) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started), or death due to any cause.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Massachusetts General Hospital

Trial Keywords

  • Lung Cancer
  • Anaplastic Lymphoma Kinase Rearrangement
  • ROS1 Rearrangement
  • Relapsed Cancer
  • Resistant Cancer
  • MET Amplification

Last Updated

February 28, 2020