Clinical Trials /

Atezolizumab Monotherapy vs Atezolizumab Plus Cobimetinib in Liver Metastases From Colorectal Cancer

NCT03340558

Description:

This study is for patients with metastatic colorectal cancer who are candidates for resection of metastases. This study will be conducted sequentially with 2 cohorts: 1.) Monotherapy Cohort and 2.) Combination Cohort Pre-metastatectomy - Monotherapy Cohort: The first 10 subjects will receive Atezolizumab 840 mg IV on Day 1 and Day 15 of each 28-day cycle. - Combination Cohort: The next 15 subjects will receive Atezolizumab 840 mg IV on Day 1 and Day 15 and Cobimetinib 60 mg PO on Days 1-21 of each 28-day cycle. Note: Cobimetinib must be held for the 7 days prior to metastatectomy. All subjects will be treated for 2 cycles (8 weeks) prior to metastatectomy Metastatectomy Subjects will undergo liver metastatectomy within 42 days of completion of Cycle 2 of pre-metastatectomy treatment. No study treatment is administered while the patient is healing after surgery. Post-metastatectomy Once the patient has healed from the surgery, adjuvant treatment may be administered at the discretion of the treating physician. Restaging following standards of care for this setting.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Withdrawn

Phase:

Phase 2

Trial Eligibility

Document

Title

    <li>Brief Title: Atezolizumab Monotherapy vs Atezolizumab Plus Cobimetinib in Liver Metastases From Colorectal Cancerli><li>Official Title: A Pilot Study Investigating the Effect of Atezolizumab Monotherapy and Atezolizumab Plus Cobimetinib on the Tumoral Immunoprofile in Liver Metastases From Colorectal Cancerli>

Clinical Trial IDs

    <li>ORG STUDY ID: Pro00085578li><li>NCT ID: NCT03340558li>

Conditions

    <li>Metastatic Colorectal Cancerli>

Interventions

<td>Atezolizumabtd><td/><td>Monotherapy Cohorttd><td>Cobimetinibtd><td/><td>Combination Cohorttd>
DrugSynonymsArms

Purpose

This study is for patients with metastatic colorectal cancer who are candidates for resection of metastases. This study will be conducted sequentially with 2 cohorts: 1.) Monotherapy Cohort and 2.) Combination Cohort Pre-metastatectomy - Monotherapy Cohort: The first 10 subjects will receive Atezolizumab 840 mg IV on Day 1 and Day 15 of each 28-day cycle. - Combination Cohort: The next 15 subjects will receive Atezolizumab 840 mg IV on Day 1 and Day 15 and Cobimetinib 60 mg PO on Days 1-21 of each 28-day cycle. Note: Cobimetinib must be held for the 7 days prior to metastatectomy. All subjects will be treated for 2 cycles (8 weeks) prior to metastatectomy Metastatectomy Subjects will undergo liver metastatectomy within 42 days of completion of Cycle 2 of pre-metastatectomy treatment. No study treatment is administered while the patient is healing after surgery. Post-metastatectomy Once the patient has healed from the surgery, adjuvant treatment may be administered at the discretion of the treating physician. Restaging following standards of care for this setting.

Trial Arms

<td>Monotherapy Cohorttd><td>Experimentaltd><td>The first 10 subjects will receive Atezolizumab 840 mg IV on Day 1 and Day 15 of each 28-day cycle. Subjects will be treated for 2 cycles before undergoing metastatectomy within 42 days of completion of Cycle 2. No study treatment is administered while subjects are healing after surgery.td><td>
    td>
<td>Combination Cohorttd><td>Experimentaltd><td>The next 15 subjects will receive Atezolizumab 840 mg IV on Day 1 and Day 15 and Cobimetinib 60 mg PO on Days 1-21 of each 28-day cycle. Cobimetinib must be held for the 7 days prior to metastatectomy. Subjects will be treated for 2 cycles before undergoing metastatectomy within 42 days of completion of Cycle 2.td><td>
    <li>Cobimetinibli>
td>
NameTypeDescriptionInterventions

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically and/or cytologically confirmed and radiographically measurable per
             RECIST v1.1 colorectal cancer with liver metastasis. Patients may have other sites of
             metastatic disease.µlµ

          2. Liver lesion safely amenable to core needle biopsy.

          3. Willing to undergo core needle biopsy of liver metastatic site.

          4. Microsatellite stable disease as determined by IHC and/or PCR.

          5. Plan for next therapeutic intervention to be surgical resection of metastatic disease.

          6. Age ≥18 years with ability to understand and willingness to provide informed consent.

          7. ECOG performance status of 0 or 1.

          8. Life expectancy of >3 months.

          9. For Combination Therapy cohort only: Able to swallow pills.

         10. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
             within 7 days prior to start of study drug and must be willing to use two methods of
             contraception, one of them being a barrier method during the study and for 3 months
             (or 6 months for subjects on Combination Therapy cohort) after last study drug
             administration.

         11. Adequate organ and marrow function as defined below:

               1. Absolute neutrophil count (ANC) ≥1500 µl

               2. WBC counts > 2500/µl

               3. Lymphocyte count ≥ 300/µl

               4. Platelets ≥ 100,000/µl

               5. Hemoglobin (Hgb) ≥ 9 g/dL

               6. Total bilirubin ≤ 1.5 x upper limit of normal (ULN); ≤ 3 x ULN for patients with
                  known Gilbert disease

               7. AST/ALT ≤ 3 x ULN without liver metastasis; ≤ 5 x ULN for patients with liver
                  metastasis

               8. Alkaline phosphatase ≤ 2.5 x ULN; ≤ 5 x ULN for patients with liver metastasis

               9. Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 ml/min on the basis of
                  the Cockcroft-Gault glomerular filtration rate estimation

              10. INR and aPTT ≤ 1.5 x ULN. Note that this applies only to patients who do not
                  receive therapeutic anticoagulation; patients receiving therapeutic
                  anticoagulation (such as low-molecular-weight heparin or warfarin) should be on a
                  stable dose.

        Exclusion Criteria:

          1. Prior therapy with anti-PD-1 or anti-PD-L1 therapeutic antibody or pathway targeting
             agents.

             a. Patients who have received prior treatment with anti-CTLA-4 may be enrolled,
             provided the following requirements are met: i. Minimum of 12 weeks from the first
             dose of anti-CTLA-4 and > 6 weeks from the last dose.

             ii. No history of severe immune-related adverse effects from anti-CTLA-4 (NCI CTCAE
             Grade 3 and 4)

          2. For Combination Therapy cohort only: Prior therapy with MEK inhibitors.

          3. Anticancer therapy, including but not limited to chemotherapy, hormonal therapy, or
             radiotherapy, within 4 weeks prior to start of study treatment; however, the following
             are allowed:

               1. Hormone-replacement therapy or oral contraceptives

               2. Herbal therapy > 1 week prior to start of study treatment (herbal therapy
                  intended as anticancer therapy must be discontinued at least 1 week prior to
                  start of study treatment)

               3. Palliative radiotherapy for bone metastases > 2 weeks prior to start of study
                  treatment

          4. Expected to require any other form of systemic or localized anticancer therapy while
             on study.

          5. Adverse events from prior anticancer therapy that have not resolved to Grade ≤ 1
             except for alopecia.

          6. Investigational agent within 4 weeks prior to start of study treatment (or within five
             half-lives of the investigational product, whichever is longer).

          7. Major surgical procedure within 28 days prior to start of study treatment or
             anticipation of need for a major surgical procedure during the course of the study.
             This does not refer to the planned liver metastatectomy that is part of the study.

          8. Malignancies other than the disease under study within 5 years prior to start of study
             treatment, with the exception of those with a negligible risk of metastasis or death
             and with expected curative outcome (such as adequately treated carcinoma in situ of
             the cervix, basal or squamous cell skin cancer, localized prostate cancer treated
             surgically with curative intent, or ductal carcinoma in situ treated surgically with
             curative intent) or undergoing active surveillance per standard-of-care management
             (e.g. chronic lymphocytic leukemia Rai stage 0, prostate cancer with Gleason score <
             6, and prostate-specific [PSA] ≤ 10 mg/mL, etc).

          9. Diagnosis of acute leukemias, accelerated/blast-phase chronic myelogenous leukemia,
             chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory
             myeloma.

         10. Prior allogenic bone marrow transplantation or prior solid organ transplantation.

         11. Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases.

             a. Patients with asymptomatic untreated CNS disease may be enrolled, provided all of
             the following criteria are met: i. Evaluable or measurable disease outside the CNS ii.
             No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of
             the optic apparatus (optic nerves and chiasm) iii. No history of intracranial
             hemorrhage or spinal cord hemorrhage iv. No ongoing requirement for dexamethasone for
             CNS disease; patients on a stable dose of anticonvulsants are permitted.

             v. No neurosurgical resection or brain biopsy within 28 days prior to start of study
             treatment b. Patients with asymptomatic treated CNS metastases may be enrolled,
             provided all the criteria listed above are met as well as the following: i.
             Radiographic demonstration of improvement upon the completion of CNS-directed therapy
             and no evidence of interim progression between the completion of CNS-directed therapy
             and the screening radiographic study ii. No stereotactic radiation or whole-brain
             radiation within 28 days prior to start of study treatment iii. Screening CNS
             radiographic study ≥ 4 weeks from completion of radiotherapy and ≥ 2 weeks from
             discontinuation of corticosteroids

         12. Serious, non-healing wound, ulcer, or bone fracture.

         13. Pregnancy, lactation, or breastfeeding

         14. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins or Chinese hamster ovary cell
             products.

         15. History of malabsorption or other condition that would interfere with absorption of
             cobimetinib.

         16. Bisphosphonate therapy for symptomatic hypercalcemia. Use of bisphosphonate therapy
             for other reasons (e.g., bone metastasis for osteoporosis) is allowed.

         17. Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis; cirrhosis; fatty liver; and inherited liver disease.

         18. History or risk of autoimmune disease, including but not limited to systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
             associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
             syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
             thyroid disease, vasculitis, or glomerulonephritis.

               1. Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
                  replacement hormone, controlled Type 1 diabetes mellitus on a stable insulin
                  regimen are eligible.

               2. Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis would
                  be excluded) are permitted provided that they meet the following conditions:

             i. Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular
             manifestations ii. Rash must cover less than 10% of the body surface area (BSA) iii.
             Disease is well controlled at baseline and only requiring low potency topical steroids
             (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide
             0.05%, aclometasone dipropionate 0.05%) iv. No acute exacerbations of underlying
             condition within the last 12 months (not requiring psoralen plus ultraviolet A
             radiation (PUVA), methotrexate, retinoids, biologic agents, oral calcineurin
             inhibitors; high potency or oral steroids)

         19. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
             organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
             pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
             tomography (CT) scan. (History of radiation pneumonitis in the radiation field
             (fibrosis) is permitted)

         20. Treatment with systemic immunostimulatory agents (including but not limited to
             interferon [IFN]-α or interleukin [IL]-2) within 6 weeks or five half-lives of the
             drug (whichever is shorter) prior to start of study treatment.

         21. Treatment with systemic immunosuppressive medications (including but not limited to
             prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
             necrosis factor [anti-TNF] agents) within 2 weeks prior to start of study treatment.

               1. Patients who have received acute, low-dose, systemic immunosuppressant
                  medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled

               2. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
                  for patients with orthostatic hypotension or adrenocortical insufficiency is
                  allowed

         22. History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C
             infection

               1. Patients with past or resolved hepatitis B infection (defined as having a
                  negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
                  [antibody to hepatitis B core antigen] antibody test) are eligible.

               2. Patients positive for hepatitis C virus (HCV) antibody are eligible only if
                  polymerase chain reaction (PCR) is negative for HCV RNA.

         23. Active tuberculosis

         24. Severe infections within 4 weeks prior to start of study treatment, including but not
             limited to hospitalization for complications of infection, bacteremia, or severe
             pneumonia.

         25. Signs or symptoms of infection within 2 weeks prior to start of study treatment

         26. Received oral or IV antibiotics within 2 weeks prior to start of study treatment

             a. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary
             tract infection or chronic obstructive pulmonary disease) are eligible

         27. Administration of a live, attenuated vaccine within 4 weeks before start of study
             treatment or anticipation that such a live, attenuated vaccine will be required during
             the study

             a. Influenza vaccination should be given during influenza season only (approximately
             October to March). Patients must not receive live, attenuated influenza vaccine (e.g.,
             FluMist®) within 4 weeks prior to start of study treatment or at any time during the
             study.

         28. History of or evidence of retinal pathology on ophthalmologic examination that is
             considered a risk factor for neurosensory retinal detachment, retinal vein occlusion
             (RVO), or neovascular macular degeneration. Patients should be excluded if they have
             the following risk factors for RVO:

               1. History of serous retinopathy

               2. History of retinal vein occlusion (RVO)

               3. Evidence of ongoing serous retinopathy or RVO at baseline

         29. History of clinically significant cardiac dysfunction, including the following:

               1. Current unstable angina

               2. Current symptomatic congestive heart failure of NYHA class 2 or higher

               3. Uncontrolled hypertension ≥ Grade 2 (patients with a history of hypertension
                  controlled with anti-hypertensives to ≤ Grade 1 are eligible).

               4. Left ventricular ejection fraction (LVEF) below institutional LLN or below 50%,
                  whichever is lower

               5. Uncontrolled arrhythmias

               6. Myocardial infarction, severe/unstable angina, symptomatic congestive heart
                  failure, cerebrovascular accident or transient ischemic attack within the
                  previous 6 months

         30. Any other diseases, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicates the use of an investigational drug or that may affect the
             interpretation of the results of render the patient at high risk from treatment
             complications.

         31. Inability to comply with study and follow-up procedures.
      
<td>Maximum Eligible Age:td><td>N/Atd><td>Minimum Eligible Age:td><td>18 Yearstd><td>Eligible Gender:td><td>Alltd><td>Healthy Volunteers:td><td>Notd>

Primary Outcome Measures

<td>Measure:td><td>Change in CD4 T cell immune infiltratestd><td>Time Frame:td><td>Subject tissue will be assessed pre-treatment (baseline) and post-treatment within 42 days after completion of Cycle 2 using metastatectomy tissue.td><td>Safety Issue:td><td/><td>Description:td><td>The change in CD4 T cell tumor infiltrates will be measured as the absolute number of infiltrates per number of high-powered fields. The paired t-test will be used to compare changes in CD4 T cells in pre- and post-treatment.td>

Secondary Outcome Measures

<td>Measure:td><td>Disease-free survivaltd><td>Time Frame:td><td>Disease-free survival will be measured from study entry up to 5 years.td><td>Safety Issue:td><td/><td>Description:td><td>The length of time after primary treatment that the subject survives without any signs or symptoms of that cancer.td>
<td>Measure:td><td>Overall Survivaltd><td>Time Frame:td><td>Overall survival will be measured from study entry up to 5 yearstd><td>Safety Issue:td><td/><td>Description:td><td>The length of time from start of treatment that the subject is alivetd>

Details

<td>Phase:td><td>Phase 2td><td>Primary Purpose:td><td>Interventionaltd><td>Overall Status:td><td>Not yet recruitingtd><td>Lead Sponsor:td><td>Niharika Mettutd>

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