Tiragolumab Plus Atezolizumab Versus Atezolizumab in the Treatment of Stage II Melanoma Patients Who Are ctDNA-positive Following Resection
Condition: Stage II Melanoma
MeSH terms: Melanoma
Intervention: Atezolizumab; Tiragolumab; Signatera Assay
Intervention description: Atezolizumab is provided by Genentech.; Tiragolumab is provided by Genentech.; To detect residual disease or to determine cancer recurrence with ctDNA
Step 2 screening (4-12 weeks after date of surgery), cycle 3 day 1, cycle 6 day 1, cycle 9 day 1, cycle 12 day 1, and end of treatment (optional)
Intervention MeSH terms: Atezolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This study's hypothesis is that patients with stage II melanoma who test positive for
      circulating tumor DNA are at a higher risk for recurrence and therefore adjuvant treatment is
      justified. In this study, the blood of consenting and eligible patients will be tested for
      ctDNA and those patients who test positive will be randomized on a 1:1 basis to either
      treatment with atezolizumab and tiragolumab or atezolizumab alone during Stage 1 of the
      study. If at least 3 patients in the atezolizumab + tiragolumab arm are shown to be ctDNA
      negative at C3D1, stage 2 of the study will begin enrollment. Stage 2 consists of 25 patients
      all enrolled to the atezolizumab + tiragolumab arm (no randomization and no atezolizumab
      monotherapy arm).Patients who test negative for ctDNA will be observed off protocol.
    

Eligibility criteria:

        Step One (Signatera Assay Development) Inclusion Criteria:

          -  Surgically resected and histologically/pathologically confirmed stage II cutaneous
             melanoma. No more than 16 weeks may elapse between final surgical resection and
             randomization. Treatment should start only after complete wound healing from the
             surgery.

          -  Participants must not have been previously treated for melanoma beyond complete
             surgical resection.

          -  At least 18 years of age.

          -  Ability to understand and willingness to sign an IRB approved written informed consent
             document (or that of legally authorized representative, if applicable).

        Step One (Signatera Assay Development) Exclusion Criteria:

          -  A history of other malignancy with the exception of malignancies for which all
             treatment was completed at least 2 years before registration and the patient has no
             evidence of disease or malignancies in situ (such as DCIS), basal cell carcinoma, or
             localized cutaneous squamous cell carcinomas.

          -  Currently receiving any other investigational agents.

          -  Prior history of pneumonitis

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to atezolizumab and tiragolumab or other agents used in the
             study.

          -  Significant cardiovascular disease (such as New York Heart Association Class II or
             greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3
             months prior to initiation of study treatment, unstable arrhythmia, or unstable
             angina.

          -  Active or history of autoimmune disease or immune deficiency, including, but not
             limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
             antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome,
             or multiple sclerosis, with the exceptions listed below:

               -  Patients with a history of autoimmune-related hypothyroidism who are on thyroid
                  replacement hormone are eligible for the study.

               -  Patients with controlled Type 1 diabetes mellitus who are on an 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

          -  Active tuberculosis.

          -  Prior allogeneic stem cell or solid organ transplantation

          -  Positive hepatitis B surface antigen (HBsAb) at screening.

          -  Positive hepatitis C virus (HCV) antibody test at screening (unless followed by a
             negative HCV RNA test).

          -  Current treatment with anti-viral therapy for HBV

          -  Positive Epstein-Barr virus (EBV) viral capsid antigen immunoglobulin M (IgM) test at
             screening. An EBV PCR test should be performed as clinically indicated to screen for
             acute infection or suspected chronic active infection. Patients with a positive EBV
             PCR test are excluded.

          -  Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including
             anti-CTLA-4, anti-PD-1, anti-TIGIT, and anti-PD-L1 therapeutic antibodies.

          -  History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
             or fusion proteins

          -  Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or
             they have a history of AIDS-defining opportunistic infection within the 12 months
             prior to registration. Concurrent treatment with effective ART according to DHHS
             treatment guidelines is recommended.

        Step Two (Randomization and Treatment) Inclusion Criteria:

          -  Positive ctDNA test.

          -  Normal bone marrow and organ function as defined below:

               -  Absolute neutrophil count ≥ 1,500/mcL

               -  Lymphocyte count ≥ 500/mcL

               -  Platelets ≥ 100,000/mcL

               -  Hemoglobin ≥ 9.0 g/dL (patients may be transfused to meet this criterion)

               -  Total bilirubin ≤ 1.5 x IULN or direct bilirubin ≤ IULN for participants with
                  total bilirubin levels > 1.5 x IULN; patients with known Gilbert disease must
                  have total bilirubin ≤ 3 x IULN

               -  AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN

               -  Alkaline phosphatase ≤ 2.5 x IULN

               -  Creatinine clearance ≥ 45 mL/min by Cockcroft-Gault

               -  Serum albumin ≥ 2.5 g/dL

               -  INR or PT ≤ 1.5 x IULN unless participant is receiving anticoagulant therapy as
                  long as PT or aPTT is within therapeutic range of intended use of anticoagulants

               -  aPTT ≤ 1.5 x IULN unless participant is receiving anticoagulant therapy as long
                  as PT or aPTT is within therapeutic range of intended use of anticoagulants

          -  ECOG performance status ≤ 1

          -  The effects of atezolizumab and tiragolumab on the developing human fetus are unknown.
             For this reason, women of childbearing potential and men must agree to use adequate
             contraception (hormonal or barrier method of birth control, abstinence) prior to study
             entry and for the duration of study participation, for 90 days after the final dose of
             tiragolumab, and for 5 months after the final dose of atezolizumab. Should a woman
             become pregnant or suspect she is pregnant while participating in this study, she must
             inform her treating physician immediately. Men treated or enrolled on this protocol
             must also agree to use adequate contraception prior to the study, for the duration of
             the study, and 90 days after completion of the study

        Step Two (Randomization and Treatment) Exclusion Criteria:

          -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
             pregnancy test within 14 days of study entry.

          -  Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
             treatment, or anticipation of need for such a vaccine during study treatment, within
             90 days after the final dose of tiragolumab, or within 5 months after the final dose
             of atezolizumab

          -  Treatment with systemic immunostimulatory agents (including, but not limited to,
             interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is
             longer) prior to initiation of study treatment.

          -  Treatment with systemic immunosuppressive medication (including, but not limited to,
             corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
             anti-tumor necrosis factor-α [TNF-α] agents) within 2 weeks prior to initiation of
             study treatment, or anticipation of need for systemic immunosuppressive medication
             during study treatment, with the following exceptions:

               -  Patients who received acute, low-dose systemic immunosuppressant medication or a
                  one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of
                  corticosteroids for a contrast allergy) are eligible for the study

               -  Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids
                  for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose
                  corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible
                  for the study.

          -  Major surgical procedure within 4 weeks prior to initiation of study treatment, or
             anticipation of need for a major surgical procedure during the study.

          -  Severe infection within 4 weeks prior to initiation of study treatment, including, but
             not limited to, hospitalization for complications of infection, bacteremia, or severe
             pneumonia, or any active infection that, in the opinion of the investigator, could
             impact patient safety

          -  Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
             of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a
             urinary tract infection or chronic obstructive pulmonary disease exacerbation) are
             eligible for the study.

          -  Treatment with systemic immunostimulatory agents (including, but not limited to,
             interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is
             longer) prior to initiation of study treatment.