Cobimetinib, Atezolizumab, and Hydroxychloroquine for the Treatment of Metastatic or Unresectable KRAS-Mutated Malignancies, MEKiAUTO Study

Inclusion Criteria

• For Phase 1 and 2, participants must have histologically confirmed KRAS-mutant malignancy that is metastatic or unresectable, and for which standard curative or meaningful life prolonging palliative measures do not exist or are no longer effective as described below. Subjects with pancreas adenocarcinoma or colorectal adenocarcinoma have specific requirements. At least 12 of the 18 evaluable patients within phase 1 should carry an active diagnosis of either pancreas or colorectal adenocarcinoma
• Histological or pathological confirmation of malignancy with a KRAS-activating mutation. Cytologic or histologic proof of malignancy needs to be verified by the treating institution pathologist, either from the initial diagnostic biopsy or from the required pre-treatment biopsy, prior to initiation of any study-related therapy. Tumor must contain an activating KRAS mutation as determined by an Food and Drug Administration (FDA) or New York State approved non-significant risk assay (within exons 2, 3, and 4). Subjects may be enrolled using prior KRAS positive result by non-FDA or New York State approved assay obtained per standard of care, but may not initiate treatment until KRAS mutation is confirmed by an FDA or New York State approved assay. FDA approved mutational analysis tests performed on blood which identify a KRAS mutation along with a biopsy which confirms tumor histology will be sufficient to meet this criteria. Please note, there is specific interest in KRAS G12R mutated patients with pancreas cancer or colorectal cancer
• Advanced disease for which no curable options are available, including but not limited to, surgery, radiation, or loco-regional therapy. Subjects who are not deemed candidates for these curative therapies will be eligible if they meet other criteria
• Prior treatments * Pancreas adenocarcinoma ** Subjects must have progressed on or be intolerant of combination therapy containing either 5-fluorouracil/capecitabine- and/or gemcitabine-based therapy. Subjects who experienced disease recurrence while receiving adjuvant chemotherapy or within three months of completing adjuvant chemotherapy are eligible * Colorectal adenocarcinoma ** Subjects must have progressed on or be intolerant of combination therapy containing 5-fluorouracil/capecitabine, and must have received oxaliplatin and irinotecan * Microsatellite instability (MSI)-high (H)/mismatch repair deficiency (dMMR) or NTRK-fusion positive tumors ** Subjects must have received prior treatment with approved drugs for tumors harboring these aberrations * Histology agnostic cancers other than pancreas and colorectal adenocarcinoma (see above; phase 1 and 2) ** Subjects must have progressed on or be intolerant of all standard of care therapies that result in a median progression free survival benefit of >= 8 weeks, or overall response rate of > 5%
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L without granulocyte colony-stimulating factor support (within 14 days prior to initiation of study treatment)
• White blood cell (WBC) count >= 2.5 x 10^9/L (2500/uL) (within 14 days prior to initiation of study treatment)
• Lymphocyte count >= 0.5 x 10^9/L (500/uL) (within 14 days prior to initiation of study treatment)
• Platelet count >= 100 x 10^9/L (100,000/uL) (within 14 days prior to initiation of study treatment)
• Hemoglobin (Hgb) > 9.0 g/dL (within 14 days prior to initiation of study treatment)
• Aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN), unless elevated secondary to biliary obstruction from the pancreas mass and amenable to decompression prior to initiation of therapy (within 14 days prior to initiation of study treatment)
• Alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN), unless elevated secondary to biliary obstruction from the pancreas mass and amenable to decompression prior to initiation of therapy (within 14 days prior to initiation of study treatment)
• Alkaline phosphatase (ALP) =< 2.5 x upper limit of normal (ULN), unless elevated secondary to biliary obstruction from the pancreas mass and amenable to decompression prior to initiation of therapy (within 14 days prior to initiation of study treatment)
• Serum total bilirubin =< 1.5 x ULN, unless in patients with known Gilbert disease (=< 3 x ULN), or unless elevated secondary to biliary obstruction from the pancreas mass and amenable to decompression prior to administration of investigational therapy (within 14 days prior to initiation of study treatment)
• Albumin >= 3.0 g/dL (within 14 days prior to initiation of study treatment)
• Creatinine within ULN or calculated creatinine clearance (CrCl) > 50 mL/min using the Cockcroft-Gault formula (within 14 days prior to initiation of study treatment)
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN except for those who are on stable anticoagulation for at least three months (within 14 days prior to initiation of study treatment)
• Measurable disease according to immune-modified (IM)-Response Evaluation Criteria in Solid Tumors (RECIST) and tumor accessible for fresh biopsy if ten adequate paired biopsied specimens have not been procured (Phase 1)
• Women of childbearing potential must have a negative serum pregnancy test at screening and must agree to use an effective form of contraception from the time of the negative pregnancy test until a minimum of 3 months after the last dose of study drug. Effective forms of contraception include abstinence, hormonal contraceptive (injectable or implantable) in conjunction with a barrier method, or a double barrier method. Women of non-child-bearing potential must have been postmenopausal for >= 1 year or surgically sterile
• Fertile men must agree to use an effective method of birth control during the study and for up to 3 months after the last dose of study drug
• Participants must be willing and able to provide written informed consent prior to any study-related procedures and to comply with all study requirements
• Participants must be able to comply with the study protocol, according to the investigator’s judgement
• Participants must have undergone lower extremity dopplers to rule out deep venous thrombosis (DVT) within the screening period, and undergo therapeutic anticoagulation if evidence of DVT is identified
• Patients deemed at increased risk of venous thromboembolism (VTE) based on primary cancer, which includes pancreas adenocarcinoma, gastric/gastroesophageal (GE) junction adenocarcinoma, or central nervous system (CNS) malignancy, and have not been taking anticoagulants, are to undergo prophylaxis anticoagulation with enoxaparin. Enoxaparin will be administered at a dose of 1 mg/kg/day to mitigate the risk of VTE. Subjects who are unable to receive enoxaparin, but deemed at increased risk of VTE will not be eligible and consultation with the principal investigator is required
• Subjects who are currently stable on full-dose anticoagulation medication for at least 8 weeks are considered eligible. However, subjects who have an increased clot burden on full-dose anticoagulation, such as central pulmonary embolism, or peripheral pulmonary embolism, and DVT within the extremities will be considered eligible only with the approval of the principal investigator

Exclusion Criteria

• Participants may not have had any treatments with investigational therapy within the 28 days prior to initiation of study treatment
• Participants may not have had radiation therapy within 2 weeks prior to initiation of study treatment. Participants may not have had previous radiotherapy to 25% or more of the bone marrow
• Participants may not have had systemic chemotherapy within 14 days or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment * In addition, the following prior treatment is not allowed during phase 1 of the study: ** Receptor tyrosine kinase inhibitors targeting MAP kinase pathway ** Any pharmacological agents inhibiting the autophagy pathway * In addition, the following prior treatment is not allowed during phase 2 of the study: ** T-cell co-stimulating agents or immune checkpoint blockade therapies, including but not limited to anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies ** Receptor tyrosine kinase inhibitors targeting MAP kinase pathway ** Any pharmacological agents inhibiting the autophagy pathway
• Participants may not initiate treatment if they have adverse events from prior anti-cancer therapy that have not resolved to grade =< 1 or better, with the exception of grade =< 2 peripheral neuropathy or any grade alopecia
• Patients currently receiving any other investigational agents
• Concomitant treatment with other anti-neoplastic agents (hormone therapy acceptable)
• Uncontrolled pleural effusion, pericardial effusion, or ascites
• Patients with symptomatic brain metastases * Subjects with untreated brain metastasis =< 1 cm can be considered eligible if deemed asymptomatic by the investigator upon consultation with the medical monitor, and do not require immediate radiation or steroids. Subjects with brain metastasis that is treated and stable for 1 month may be considered eligible if they are asymptomatic and on stable dose of steroids, or if they do not require steroids following successful local therapy
• Uncontrolled hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy
• Participants may not have undergone major surgery or experienced significant traumatic injury within 14 days prior to initiating study treatment, or be recovering from a procedure related to adverse events of =< grade 1
• Active or history of autoimmune disease or immune deficiency * Includes, but is not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions: ** Patients with a history of autoimmune-related hypothyroidism who are on stable thyroid-replacement hormone are eligible for the study ** Patients with controlled type 1 diabetes mellitus who are on a stable insulin regimen are eligible for the study ** Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: *** Rash must cover < 10% of body surface area *** Disease is well-controlled at baseline and requires only low-potency topical corticosteroids *** No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
• History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan (history of radiation pneumonitis in the radiation field [fibrosis] is permitted)
• Positive for human immunodeficiency virus (HIV) at screening or any time prior to screening * Patients without prior positive HIV test result will undergo an HIV test at screening, unless not permitted under local regulations
• Active hepatitis B virus (HBV) infection (chronic or acute) * Defined as having a positive hepatitis B surface antigen (HBsAg) test at screening. Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody test at screening, are eligible for the study
• Active hepatitis C virus (HCV) infection * Defined as positive HCV antibody test followed by a positive HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test
• Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, fatty liver disease, and inherited liver disease
• Active tuberculosis
• Patients may not have had a severe infection within 4 weeks prior to initiation of study treatment. This includes, but is not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. However, patients who were admitted for biliary tract infection due to bile duct obstruction at time of diagnosis must have a functioning biliary stent (as evidenced by declining total bilirubin and =< 2 x ULN) and resolved infection (defined by normalization of elevated white blood cell count, absence of signs of infection) and completion of an antibiotic course (at least a seven-day course) prior to initiation of therapy
• Patients may not have been treated with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to initiation of study treatment, except for biliary tract infection due to bile duct obstruction from the pancreas mass. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
• Patient may not have significant cardiovascular disease (such as New York Heart Association class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 12 months prior to initiation of study treatment, seizure disorder, uncontrolled hypertension, or unstable arrhythmia or unstable angina within 3 months prior to initiation of study treatment
• Left ventricular ejection fraction below institutional lower limit of normal or below 50%, whichever is lower
• Baseline Fridericia's correction formula (QTcF) >= 450 ms (males) or >= 470 ms (females)
• Grade >= 3 hemorrhage or bleeding event within 28 days prior to initiation of study treatment
• Prior autologous stem cell, allogeneic stem cell, or solid organ transplantation
• Patient may not have a history of malignancy other than pancreatic ductal adenocarcinoma (PDA) within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year overall survival of > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer
• Patients may not have been treated with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipate the need for such a vaccine during treatment with atezolizumab or within 5 months after the last dose of atezolizumab
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known allergy or hypersensitivity to 4-aminoquinoline compounds or any of the study drug excipients
• Patients may not have been treated with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study treatment, or anticipate the need for systemic immunosuppressive medication during the course of the study, with the following exceptions: * Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study if receiving equivalent to < 10 mg of prednisone daily * Patients who received a one-time pulse dose of systemic immunosuppressant medication are eligible for the study after approval from the principal investigator
• Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications
• Patients may not have a 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. Specifically, patients will be excluded from study participation if they currently are known to have any risk factors for RVO, including: * Glaucoma with intraocular pressure >= 21 mmHg; * Grade >= 2 serum cholesterol; * Grade >= 2 hypertriglyceridemia; * Grade >= 2 uncontrolled hypertension (patients with a history of hypertension controlled with anti-hypertensive medication to grade =< 1 are eligible)
• Pregnant women are excluded from this study because there is an unknown, but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with these agents; breastfeeding should be discontinued
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications in the opinion of the treating investigator
• Common CYP3A4 inhibitors and inducers. These include anticonvulsants, mycin antimicrobials, and antiretrovirals. Some common examples include inhibitors, such as erythromycin, fluoxetine, gemfibrozil, and inducers, such as rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine. Concomitant treatment is permitted if the medication is not expected to interfere with the evaluation of safety or efficacy of the study drug. During the study, if the use of any concomitant treatment becomes necessary (e.g., for treatment of an adverse event), the treatment must be recorded on the electronic case report form (eCRF), including the reason for treatment, generic name of the drug, dosage, route, and start and stop dates of administration
• Uncontrolled psoriasis, porphyria, proximal myopathy or neuropathy
• Subjects hospitalized for depression within the past 2 years, or who have prior suicidal attempts will be excluded
• Gluocose-6-phosphate dehydrogenase (G-6-PD) deficiency
• History of connective tissue disorders (e.g., lupus, scleroderma, arteritis nodosa)
• Subjects on greater than once daily dose of antacid therapy
• Concomitant use of any of the following drugs: * Digoxin * Pharmacological agents known to prolong QT interval * Mefloquine or other agents which may lower the convulsive threshold * Antiepileptics * Methotrexate * Cyclosporine * Ampicillin * Cimetidine