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

This is a Phase I/II clinical trial. A Phase I clinical trial tests the safety of
investigational drugs or new combinations of approved drugs. In addition, a Phase I study
tries to define the appropriate dose of the investigational drugs to use for further studies.
"Investigational" means that the drugs are being studied. Following the phase I study,
additional participants will be enrolled to the Phase II component. The phase II component
will test the safest doses of alectinib and cobimetinib (as identified in the Phase I
component) in a larger group of patients.

The FDA (the U.S. Food and Drug Administration) has approved alectinib as a treatment option
for this disease.

The FDA has not approved cobimetinib as a treatment for this specific disease. However,
cobimetinib is approved for treatment of melanoma, another type of cancer.

Alectinib is an oral ALK inhibitor made by the pharmaceutical company Genentech. The term ALK
inhibitor means that alectinib targets the abnormal ALK protein that is causing your lung
cancer cells to grow. Alectinib has been tested in other clinical research studies and
results show that the drug may help stop the growth and spread of ALK+ lung cancer cells.

Cobimetinib is an oral inhibitor of MEK, a signaling protein that can cause some types of
lung cancer to grow. Cobimetinib is also made by Genentech. Laboratory studies suggest that
ALK and MEK may work together to help ALK+ lung cancer cells grow. In the laboratory,
combination treatment with drugs targeting ALK and MEK prevented lung cancer cells from
growing. It is possible that combination treatment with alectinib and cobimetinib will work
better than alectinib alone to control the spread of the cancer.

In this research study, the investigators are trying to determine whether the combination of
alectinib and cobimetinib is safe and well tolerated. This study will help determine the
doses of the drugs that should be used in the Phase II portion of this study. Another purpose
of this study is to determine whether adding cobimetinib to alectinib is effective for
treating lung cancer that has already stopped responding to alectinib alone. In order to help
understand why the cancer may have stopped responding to alectinib and whether treatment with
the two drugs effectively blocks growth signals, all participants in this study will have
periodic blood collections and undergo multiple biopsies.

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.