A Phase IB/II Study of Lorlatinib Combinations in Anaplastic Lymphoma Kinase-Rearranged Lung Cancer

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

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 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:

- 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 and TNO155 groups 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.