A Phase IB/II Study of Alectinib Combined with Cobimetinib in Advanced ALK-Rearranged (ALK+) NSCLC

This research study is studying a drug combination as a possible treatment for anaplastic
lymphoma kinase-positive (ALK+) non-small cell lung cancer.

The drugs involved in this study are:

- Alectinib

- Cobimetinib

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 NSCLC (Stage IV,
AJCC v7.0) that carries an ALK rearrangement, as determined by the Food and Drug
Administration (FDA)-approved fluorescence in-situ hybridization (FISH) test, using
Vysis® ALK Break apart FISH Probe, or the Ventana® immunohistochemistry (IHC) test.
Diagnosis using next generation sequencing (NGS) via a local diagnostic test will be
accepted for enrollment but will need to be confirmed with either FISH or IHC.

- For the expansion cohort: Patients must have had disease progression on alectinib
(including patients who received alectinib as first-line treatment). Subsequent
anti-neoplastic therapy (including other ALK inhibitors or chemotherapy) after
progression on alectinib is not permitted. Note: patients in the dose-finding
portion of the study may have received other anti-neoplastic therapy after
progression on alectinib.

- 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.

- Eastern Cooperative Group (ECOG) performance status ≤ 2 for patients treated in the
expansion phase. ECOG PS ≤ 1 is required for participants in the dose-finding
portion of the study.

- Life expectancy of greater than 12 weeks

- Patient willingness and disease accessible to pre-treatment, on-treatment tumor, and
progression biopsies (core biopsies). A cell block from a pleural effusion may be
substituted for a core biopsy.

- 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.

- For participants in the dose-finding phase, a minimum washout period of at least 5
half-lives between the last dose of tyrosine kinase inhibitor (TKI) therapy and the
first dose of study treatment is required. For patients on crizotinib, a 7 day
washout is sufficient. A shorter washout period may be considered in the event of
disease flare, after discussion with the Sponsor. No washout is required if the most
recent anti-neoplastic therapy is alectinib.

- Patients must have recovered from treatment toxicities to ≤ Grade 1 or to their
pretreatment levels except for adverse events (AEs) that in the investigator's
judgment do not constitute a safety risk for the patient.

- Patients can either be chemotherapy-naive or have received platinum-based
chemotherapy for locally advanced or metastatic disease. Acute effects of therapy
must have resolved to baseline severity or to CTCAE grade ≤1 except for AEs that in
the investigator's judgment do not constitute a safety risk for the patient.
Patients who have received prior treatment with checkpoint inhibitors are eligible.

- 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 post-ovulation 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 central nervous system (CNS)
lesions are allowed in this trial as long as the CNS is not a site of progressive
disease on alectinib monotherapy. If the CNS is a site of progressive disease on
alectinib monotherapy, treatment of CNS lesions is required for enrollment.

- 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 2 weeks
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 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
alectinib will be required to undergo CNS radiation to meet eligibility.

Exclusion Criteria:

- Participants who have had chemotherapy 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.

- Participants who experienced progression of CNS lesions on alectinib who have not
received local CNS therapies (radiation, surgery) to address the lesions. CNS
imaging obtained at least 21 days after completion of radiation is required for
confirmation of response.

- 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 7 days prior to study entry. Whole brain radiation and
radiation for leptomeningeal metastasis must have been completed at least 2 weeks
prior to study entry. Acute effects of radiation must have resolved to baseline
severity or to CTCAE grade ≤1 except for AEs that in the investigator's judgment do
not constitute a safety risk for the patient.

- Participants with uncontrolled tumor-related pain.

- Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases
or metastases causing nerve impingement) should be treated prior to enrollment.

- Asymptomatic metastatic lesions whose further growth would likely cause
functional deficits or intractable pain (e.g., epidural metastases that are not
currently associated with spinal cord compression) should be considered for
loco-regional therapy if appropriate prior to enrollment.

- Patients who are receiving denosumab prior to enrollment who are not willing and/or
eligible to switch to a bisphosphonate while on study.

- Pregnant or lactating women.

- History of hypersensitivity to alectinib or any of its excipients. In addition,
subjects who are unable to tolerate the 600 mg twice daily (BID) dose of alectinib
will not be permitted to enroll unless doses of alectinib below the entry level are
being investigated (e.g. dose level -1 and -2) and they have previously tolerated
alectinib monotherapy at the dose being investigated.

- Participants with prior allogeneic stem cell or solid organ transplantation.

- 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

- Positive test for human immunodeficiency virus (HIV) or history of active
tuberculosis

- Current use or anticipated need for food or drugs that are known strong or moderate
CYP3A4 inhibitors, including their administration within 2 weeks prior to the first
study treatment (ie, strong CYP3A4 inhibitors: grapefruit juice or
grapefruit/grapefruit related citrus fruits [eg, 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). For participants in the dose escalation portion, no CYP3A4 inhibitors
should be administered during the first 21 days of the study, regardless of
strength.

- Current use or anticipated need for drugs that are known strong or moderate CYP3A4
inducers including their administration within 2 weeks prior to the first study
treatment (ie, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin,
rifapentin, clevidipine, St. John's Wort). For participants in the dose escalation
portion, no CYP3A4 inducers should be administered during the first 21 days of the
study, regardless of strength.

- Current symptomatic congestive heart failure or history of symptomatic congestive
heart failure in the preceding 3 months, defined as New York Heart Association
Classification 2- 4

- 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/uL (granulocyte colony-stimulating
factor support should not be used within 2 weeks prior to Cycle 1, Day 1).

- Platelet count < 100,000/uL

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

- INR and aPTT > 1.5 x ULN (upper limit of normal)

- This applies only to patients who are not receiving therapeutic
anticoagulation. Patients receiving therapeutic anticoagulation should be 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:

- Alanine aminotransferase and asparate aminotransferase (ALT or AST) > 3x ULN
(or > 5x ULN for patients with concurrent liver metastasis) confirmed on two
consecutive measurements OR

- Serum bilirubin > 1.5 x ULN. Patients with known Gilbert's disease who have a
serum bilirubin level > 3 x ULN may be enrolled.

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

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

- 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. Patients will be excluded from study participation if they are
currently known to have any of the following risk factors for RVO:

- Glaucoma with intraocular pressure ≥ 21 mmHg

- Grade ≥ 2 serum cholesterol (patients with a history of elevated cholesterol
controlled with lipid lowering medication to Grade ≤ 1 are eligible)

- Grade ≥ 2 hypertriglyceridemia (patients with a history of elevated cholesterol
controlled with lipid lowering medication to Grade ≤ 1 are eligible)

- Grade ≥ 2 or symptomatic hyperglycemia (fasting). Hyperglycemia may be
corrected with medications to Grade ≤ 1.

- Grade ≥ 2 uncontrolled hypertension (patients with a history of hypertension
controlled with anti-hypertensive medication to Grade ≤ 1 are eligible)

- Major surgical procedure other than for diagnosis 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,
ductal carcinoma in-situ/lobular carcinoma in-situ (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 mitogen activated kinase pathway (MAPK) inhibitor

- Allergy or hypersensitivity to components of the cobimetinib formulation

- 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.