Clinical Trials /

Study of Combination Therapy With the MEK Inhibitor, Cobimetinib, Immune Checkpoint Blockade, Atezolizumab, and the AUTOphagy Inhibitor, Hydroxychloroquine in KRAS-mutated Advanced Malignancies

NCT04214418

Description:

This research study is for patients with an advanced cancer that carries a mutation in a gene called KRAS. Genes are parts of our DNA which carry instructions for a cell (the smallest component of an body part). In many cancers, the KRAS gene contains errors (mutations) which allows the tumors to grow. The purpose of this study is to determine if combination treatment with atezolizumab, cobimetinib, and hydroxychloroquine is safe, and if it will decrease the size of the tumor and prolong life in patients whose tumors contain this mutation. Cobimetinib and atezolizumab are both approved by the FDA for use in other cancers, but not in some cancer types being studied in this trial. Hydroxychloroquine is FDA approved to treat malaria and other conditions, but has also not been approved for these cancer types. Preliminary results have shown that this combination of drugs is effective at killing cancer cells and shrinking tumors in several KRAS-mutated cancers in animals.

Related Conditions:
  • Adenocarcinoma
  • Cancer
  • Colorectal Adenocarcinoma
  • Pancreatic Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Combination Therapy With the MEK Inhibitor, Cobimetinib, Immune Checkpoint Blockade, Atezolizumab, and the AUTOphagy Inhibitor, Hydroxychloroquine in KRAS-mutated Advanced Malignancies
  • Official Title: Phase 1/2 Open-label Study of Combination Therapy With the MEK Inhibitor, Cobimetinib, Immune Checkpoint Blockade, Atezolizumab, and the AUTOphagy Inhibitor, Hydroxychloroquine in KRAS-mutated Advanced Malignancies

Clinical Trial IDs

  • ORG STUDY ID: AAAS4165
  • SECONDARY ID: ML41472
  • NCT ID: NCT04214418

Conditions

  • Gastrointestinal Cancer

Interventions

DrugSynonymsArms
CobimetinibPhase 1: MTD
HydroxychloroquinePhase 1: MTD
AtezolizumabTECENTRIQ, MPDL3280APhase 1: MTD

Purpose

This research study is for patients with an advanced cancer that carries a mutation in a gene called KRAS. Genes are parts of our DNA which carry instructions for a cell (the smallest component of an body part). In many cancers, the KRAS gene contains errors (mutations) which allows the tumors to grow. The purpose of this study is to determine if combination treatment with atezolizumab, cobimetinib, and hydroxychloroquine is safe, and if it will decrease the size of the tumor and prolong life in patients whose tumors contain this mutation. Cobimetinib and atezolizumab are both approved by the FDA for use in other cancers, but not in some cancer types being studied in this trial. Hydroxychloroquine is FDA approved to treat malaria and other conditions, but has also not been approved for these cancer types. Preliminary results have shown that this combination of drugs is effective at killing cancer cells and shrinking tumors in several KRAS-mutated cancers in animals.

Detailed Description

      The overall objective of this study is to investigate the safety and preliminary efficacy of
      combination therapy with cobimetinib and hydroxychloroquine, with or without atezolizumab in
      patients with KRAS-mutated advanced malignancies. Given that the pre-clinical and clinical
      benefit from this combination is from within PDAC animal models and human subjects with PDAC
      and duodenal cancer, we will include at least 12 of the 18 evaluable subjects from PDAC
      and/or colorectal malignancies. The phase 2 portion of the study will be amended after
      preliminary safety and efficacy results from phase 1 and other ongoing clinical trials have
      been analyzed and a summary incorporated within the protocol as an amendment including a
      rationale of the cohorts to be tested. The amendment will be submitted to the Scientfic
      Review Committee at CUIMC for approval prior to activation of phase 2 portion of the study.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1: MTDExperimentalSubjects will be treated with combination therapy at the designated dose levels: Dose 1 - Hydroxychloroquine 600mg twice per day, Cobimetinib 40mg, no Atezolizumab Dose 2 - Hydroxychloroquine 600mg twice per day, Cobimetinib 40mg, Atezolizumab 840mg Dose 3 - Hydroxychloroquine 600mg twice per day, Cobimetinib 60mg, Atezolizumab 840mg
  • Cobimetinib
  • Hydroxychloroquine
  • Atezolizumab
Phase 2: Cohort 1ExperimentalAdvanced Pancreas Adenocarcinoma (N = 23-67) subjects will receive study treatment based on the MTD determined from Phase 1
  • Cobimetinib
  • Hydroxychloroquine
  • Atezolizumab
Phase 2: Cohort 2ExperimentalAdvanced Colorectal Adenocarcinoma (N = 20-34) subjects will receive study treatment based on the MTD determined from Phase 1
  • Cobimetinib
  • Hydroxychloroquine
  • Atezolizumab
Phase 2: Cohort 3ExperimentalHistology Agnostic Adenocarcinoma (N = 23-56) subjects will receive study treatment based on the MTD determined from Phase 1
  • Cobimetinib
  • Hydroxychloroquine
  • Atezolizumab

Eligibility Criteria

        Inclusion Criteria:

          1. 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 which was tested by a CLIA certified
             laboratory (within exons 2, 3, and 4).

          2. Extent of disease Advanced disease for which no curable options are available.
             Subjects who are not deemed candidates for these curative therapies will be eligible
             if they meet other criteria.

          3. 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.

               -  MSI-H/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%.

          4. ECOG performance status of 0 or 1

          5. Age ≥18 years

          6. Adequate hematological and end-organ function (test results from within 14 days prior
             to initiation of study treatment):

               -  ANC ≥ 1.5 x 109/L without granulocyte colony-stimulating factor support

               -  WBC count ≥ 2.5 x 109/L

               -  Lymphocyte count ≥ 0.5 x 109/L

               -  Platelet count ≥ 100 x 109/L without transfusion

               -  Hgb > 9.0 g/dL

               -  AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5X upper limit of normal (ULN),
                  unless elevated secondary to bilary obstruction from the pancreas mass and
                  amenable to decompression prior to initiation of therapy

               -  Serum total bilirubin ≤ 1.5X ULN, unless in patients with known Gilbert disease
                  (≤ 3X ULN), or unless elevated secondary to bilary obstruction from the pancreas
                  mass and amenable to decompression prior to administration of investigational
                  therapy

               -  Albumin ≥ 3.0g/dL

               -  Creatinine within ULN or calculated creatinine clearance (CrCl) >50 mL/min using
                  the Cockcroft-Gault formula

               -  INR and aPTT ≤ 1.5X ULN except for those who are on stable anticoagulation for at
                  least three months.

          7. Measurable disease according to IM-RECIST and tumor accessible for fresh biopsy if ten
             adequate paired biopsied specimens have not been procured (Phase 1)

          8. Negative pregnancy test Women of child-bearing 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. Women of non-child-bearing potential must have been
             postmenopausal for ≥ 1 year or surgically sterile.

          9. Birth control agreement 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.

         10. Informed consent Participants must be willing and able to provide written informed
             consent prior to any study-related procedures and to comply with all study
             requirements.

         11. Ability to comply Participants must be able to comply with the study protocol,
             according to the investigator's judgement.

         12. DVT testing 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.

         13. VTE testing Patients deemed at increased risk of venous thromboembolism (VTE) based on
             primary cancer, which includes pancreas adenocarcinoma, gastric/GE junction
             adenocarcinoma, or CNS malignancy, are to undergo prophylaxis anticoagulation with
             enoxaparin. 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.

         14. Anticoagulation treatment Subjects who are 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 will be considered eligible only
             with the approval of the Principal Investigator.

        Exclusion Criteria:

          1. Prior treatment with investigational therapy. Participants may not have had any
             treatments with investigational therapy within the 28 days prior to initiation of
             study treatment.

          2. Prior radiation therapy 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.

          3. Prior Therapy 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

               -  Receptor tyrosine kinase inhibitors targeting MAP kinase pathway;

               -  Any pharmacological agents inhibiting the autophagy pathway.

          4. Adverse events from prior anti-cancer therapy 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.

          5. Patients currently receiving any other investigational agents

          6. Concomitant treatment with other anti-neoplastic agents (hormone therapy acceptable)

          7. Uncontrolled pleural effusion, pericardial effusion, or ascites

          8. 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.

          9. Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of
             bisphosphonate therapy.

         10. Recent major surgery or significant traumatic injury 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.

         11. Active or history of autoimmune disease or immune deficiency

             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 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.

         12. History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing
             pneumonia, 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].

         13. Positive for 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.

         14. 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.

         15. 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.

         16. Known clinically significant liver disease

         17. Active tuberculosis

         18. Severe infection 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 ≤ 2X 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.

         19. Recent antibiotic treatment 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 are eligible for the study.

         20. Significant cardiovascular disease Patient may not have significant cardiovascular
             disease 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.

         21. Left ventricular ejection fraction below institutional lower limit of normal or below
             50%, whichever is lower

         22. Baseline QTcF ≥ 450 ms (males) or ≥ 470 ms (females)

         23. Grade ≥ 3 hemorrhage or bleeding event within 28 days prior to initiation of study
             treatment

         24. Prior autologous stem cell, allogeneic stem cell, or solid organ transplantation

         25. History of malignancy Patient may not have a history of malignancy other than PDA
             within 2 years prior to screening, with the exception of those with a negligible risk
             of metastasis or death.

         26. Recent vaccination 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.

         27. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
             or fusion proteins

         28. Known allergy or hypersensitivity to 4-aminoquinoline compounds or any of the study
             drug excipients

         29. Recent immunosuppressive treatment

             Patients may not have been treated with systemic immunosuppressive medication 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, 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 < 10mg 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.

         30. Inability to swallow medication or malabsorption condition that would alter the
             absorption of orally administered medications

         31. History of retinal pathology

             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).

         32. Pregnancy Pregnant women are excluded from this study because there is an unknown, but
             potential risk for AEs in nursing infants secondary to treatment of the mother with
             these agents; breastfeeding should be discontinued.

         33. Other contraindicated conditions 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.

         34. Concomitant strong CYP3A4 inhibitors and inducers 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, the treatment must be recorded on the eCRF.

         35. Uncontrolled psoriasis, porphyria, proximal myopathy or neuropathy

         36. Severe depression Subjects hospitalized for depression within the past 2 years, or who
             have prior suicidal attempts will be excluded.

         37. Gluocose-6-phosphate dehydrogenase deficiency

         38. History of connective tissue disorders

         39. Subjects on greater than once daily dose of antacid therapy

         40. 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Estimated maximum tolerated dose
Time Frame:16 weeks
Safety Issue:
Description:Time-to-event continue reassessment method (TITE-CRM)

Secondary Outcome Measures

Measure:Phase 1: Safety profile of drug combination
Time Frame:5 years
Safety Issue:
Description:AEs and SAEs
Measure:Phase 2: Progression free and overall survival
Time Frame:5 years
Safety Issue:
Description:Kaplan-Meier methodology for all patients and those assigned to the estimated MTD at the end of the trial
Measure:Phase 2: Frequency of radiographic response
Time Frame:16 weeks
Safety Issue:
Description:Best overall response rate (CR+PR)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Columbia University

Last Updated

December 27, 2019