Clinical Trials /

A Phase II Trial of PD-L1 Therapy Combined With Anti-VEGF Therapy in Unresectable or Metastatic Melanoma

NCT04356729

Description:

This research study is studying a combination of two drugs that change the immune system and tumor as a possible treatment for metastatic or unresectable stage III or IV cutaneous melanoma. The names of the study drugs involved in this study are: - Atezolizumab - Bevacizumab

Related Conditions:
  • Cutaneous Melanoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase II Trial of PD-L1 Therapy Combined With Anti-VEGF Therapy in Unresectable or Metastatic Melanoma
  • Official Title: A Phase II Trial of PD-L1 Therapy Combined With Anti-VEGF Therapy in Unresectable or Metastatic Melanoma

Clinical Trial IDs

  • ORG STUDY ID: 19-604
  • NCT ID: NCT04356729

Conditions

  • Clinical Stage III Cutaneous Melanoma AJCC v8
  • Stage IV Melanoma
  • Unresectable Stage III Cutaneous Melanoma
  • Unresectable Stage IV Cutaneous Melanoma

Interventions

DrugSynonymsArms
AtezolizumabTecentriqAtezolizumab and Bevacizumab
BevacizumabAvastin, MvasiAtezolizumab and Bevacizumab

Purpose

This research study is studying a combination of two drugs that change the immune system and tumor as a possible treatment for metastatic or unresectable stage III or IV cutaneous melanoma. The names of the study drugs involved in this study are: - Atezolizumab - Bevacizumab

Detailed Description

      The research study procedures include screening for eligibility, study treatment including
      evaluations, a biopsy, and follow up visits.

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational drug to learn whether the drug works in treating a
      specific disease. "Investigational" means that the drug is being studied. The U.S. Food and
      Drug Administration (FDA) has not approved atezolizumab for this specific disease but it has
      been approved for other uses. The U.S. Food and Drug Administration (FDA) has not approved
      bevacizumab for this specific disease but it has been approved for other uses.

      Atezolizumab and bevacizumab are types of immunotherapy. Immunotherapy works by encouraging
      the body's own immune system to attack the cancer cells and stop the growth of cancer.
      Atezolizumab and bevacizumab work by stopping various molecules on cancer cells and body
      cells from working against the immune system's natural fight against cancer.
    

Trial Arms

NameTypeDescriptionInterventions
Atezolizumab and BevacizumabExperimentalThe research study procedures include screening for eligibility, study treatment including evaluations, a biopsy, and follow up visits. Atezolizumab will be administered intravenously at a fixed predetermined dose every three weeks Bevacizumab will be administered intravenously at a fixed predetermined dose every three weeks, with 21 consecutive days defined as a treatment cycle. Treatment will be administered on an outpatient basis Study treatment will continue until study doctors decide to stop therapy due to criteria which may include disease progression, adverse events or changes in condition. Participants will be followed for survival health information following treatment until the study ends, which could be approximately 5 years from start of treatment
  • Atezolizumab
  • Bevacizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have histologically or cytologically confirmed metastatic or
             unresectable stage III or IV cutaneous melanoma.

          -  PD-L1 negative staining in at least one biopsy sample.

          -  Age ≥ 18 years

          -  ECOG performance status ≤ 2 (Karnofsky ≥60%, see Appendix A)

          -  Participants may have received any number of prior therapies for treatment of their
             cutaneous melanoma, excluding prior treatment with anti-PD-L1 therapeutic antibodies
             or bevacizumab.

          -  Participants must have measurable disease per RECIST v1.1.

          -  Participants must have availability of a representative tumor specimen for exploratory
             biomarker research.

          -  Participants must have normal organ and marrow function as defined below:

               -  lymphocyte count ≥ 500/mcL

               -  absolute neutrophil count ≥ 1,500/mcL without granulocyte colony-stimulating
                  factor support

               -  platelets* ≥100,000/mcL

               -  hemoglobin* ≥9 g/dL

               -  serum bilirubin ≤1.5 x ULN with the following exception: participants with known
                  Gilbert's Disease: serum bilirubin level ≤ 3x ULN

               -  AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN, with the following exceptions:
                  Participants with documented liver metastases: AST and ALT ≤ 5 x ULN

               -  alkaline phosphatase (ALP) ≤2.5 × institutional ULN, with the following
                  exceptions:

               -  participants with documented liver or bone metastases: ALP ≤ 5 x ULN

               -  serum creatinine ≤ 1.5 x ULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 for
                  participants with creatinine levels above institutional normal.

               -  serum albumin ≥ 2.5 g/dL

          -  For participants not receiving therapeutic anticoagulation: INR or aPTT ≤1.5 ULN

          -  Urine dipstick for proteinuria < 2+ (within 7 days prior to Cycle 1 Day 1).
             Participants discovered to have ≥ 2 + proteinuria on dipstick urinalysis at baseline
             should undergo a 24-hour urine collection and must demonstrate < 1 g of protein in 24
             hours. Note: Participants cannot be transfused to meet this criterion

          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per
             year during the treatment period and for 5 months after the last dose of atezolizumab,
             and 6 months after the last dose of bevacizumab.

          -  Examples of contraceptive methods with a failure rate of < 1 % per year include
             bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit
             ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

          -  The reliability of sexual abstinence should be evaluated in relation to the duration
             of the clinical trial and 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.

          -  For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
             a condom, and agreement to refrain from donating sperm, as defined below: With female
             partners of childbearing potential or pregnant female partners, men must remain
             abstinent or use a condom during the treatment period and for 5 months after the last
             dose of atezolizumab and 6 months after the last dose of bevacizumab, to avoid
             exposing the embryo. Men must refrain from donating sperm during this same period. The
             reliability of sexual abstinence should be evaluated in relation to the duration of
             the clinical trial and 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.

          -  Ability to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria:

          -  Participants with symptomatic, untreated, or actively progressing CNS metastases will
             be excluded. If a participant has a known history of treated CNS lesions, they are
             eligible provided that all of the following criteria are met:

          -  Measurable disease, per RECIST v1.1, must be present outside the CNS.

          -  The participant has no history of intracranial hemorrhage or spinal cord hemorrhage.

          -  Metastases are limited to the cerebellum or the supratentorial region (i.e., no
             metastases to the midbrain, pons, medulla, or spinal cord).

          -  There is no evidence of interim progression between completion of CNS-directed therapy
             and the screening brain scan

          -  The participant has not received stereotactic radiotherapy within 7 days prior to
             initiation of study treatment or whole-brain radiotherapy within 14 days prior to
             initiation of study treatment.

          -  The participant has no ongoing requirement for corticosteroids as therapy for CNS
             disease. Anticonvulsant therapy at a stable dose is permitted. Asymptomatic patients
             with CNS metastases newly detected at screening are eligible for the study after
             receiving radiotherapy or surgery, with no need to repeat the screening brain scan.

          -  History of leptomeningeal disease.

          -  Uncontrolled tumor-related pain.

               -  NOTE: Participants requiring pain medication must be on a stable regimen at study
                  entry.

               -  Symptomatic lesions amendable to palliative radiotherapy (e.g., bone metastases
                  or metastases causing nerve impingement) should be treated prior to enrollment.
                  Participants should be recovered from the effects of radiation. There is no
                  required minimum recovery period.

               -  Asymptomatic metastatic lesions that would likely cause functional deficits or
                  intractable pain with further growth (e.g., epidural metastasis that is not
                  currently associated with spinal cord compression) should be considered for
                  loco-regional therapy if appropriate prior to enrollment.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to atezolizumab and/or bevacizumab.

          -  Uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium or calcium >
             12 mg/dL or corrected serum calcium > ULN)

          -  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's syndrome, Guillain-Barré syndrome,
             or multiple sclerosis with the following exceptions:

               -  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.

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

          -  Participants who test positive for HIV at time of screening are ineligible because of
             the increased risk of lethal infections when treated with marrow-suppressive therapy.

          -  Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a
             positive hepatitis B surface antigen (HBsAg) test at screening. Participants with a
             negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at
             screening are eligible for the study.

          -  Active hepatitis C virus (HCV) infection, defined as a positive HCV antibody test
             followed by a positive HCV RNA test at screening. The HCV RNA test will be performed
             only for participants who have a positive HCV antibody test.

          -  Participants with active tuberculosis will be excluded.

          -  Significant cardiovascular disease, such as a 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.

          -  Major surgical procedure other than for diagnosis within 4 weeks prior to initiation
             of study treatment, or anticipation of need for a major surgical procedure during the
             course of the study.

          -  History of other malignancy within 2 years prior to screening, with the exception of
             those with a negligible risk of metastasis or death (e.g., 5-year OS 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.

          -  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.

          -  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.

          -  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.

          -  Prior allogeneic stem cell or solid organ transplantation.

          -  Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
             treatment, or anticipation of need for such a vaccine during the course of the study
             or within 5 months after the last dose of atezolizumab.

          -  Treatment with investigational therapy within 28 days prior to initiation of study
             treatment.

          -  Prior treatment with bevacizumab or prior PD-L1 targeted therapy.

          -  Treatment with systemic immunostimulatory agents (including, but not limited
             to,interferon and interleukin 2 [IL-2]) within 4 weeks or five half-lives of the drug
             (whichever is shorter) prior to initiation of study treatment.

          -  Treatment with systemic immunosuppressive medication (including, but not limited to,
             corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
             anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or
             anticipation of need for systemic immunosuppressive medication during the course of
             the study, 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 on physiologic replacement doses of steroids less than 10mg daily
                  prednisone equivalent are allowed. Higher replacement doses should be discussed
                  with the overall PI to determine if patient can be included on the trial.

               -  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.

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

          -  Known hypersensitivity to Chinese hamster ovary cell products or to any component of
             the atezolizumab formulation.

          -  Known allergy or hypersensitivity to any component of the bevacizumab formulation.

          -  Inadequately controlled arterial hypertension (defined as systolic blood pressure [BP]
             > 150 mm Hg and/or diastolic BP >100 mmHg), based on an average of at least three BP
             readings at two or more sessions. Anti-hypertensive therapy to achieve these
             parameters is allowed.

          -  History of hypertensive crisis or hypertensive encephalopathy.

          -  Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
             recent peripheral arterial thrombosis) within 6 months prior to Cycle 1 Day 1.

          -  History of hemoptysis (≥ 2.5 mL of bright red blood per episode) within 1 month prior
             to Cycle 1 Day 1.

          -  Evidence of bleeding diathesis or significant coagulopathy (in the absence of
             therapeutic anticoagulation).

          -  Current or recent (within 10 days of Cycle 1 Day 1) use of aspirin (> 325 mg/day) or
             current or recent treatment with dipyramidole, ticlopidine, clopidogrel, and
             cilostazol.

          -  Current or recent (within 10 days prior to Cycle 1 Day 1) use of full-dose oral or
             parenteral anticoagulants or thrombolytic agents for therapeutic purpose (as opposed
             to prophylactic). Prophylactic anticoagulation for the patency of venous access
             devices is allowed provided the activity of the agent results in an INR < 1.5 x ULN
             and aPTT is within normal limits (according to the institutional standards) within 14
             days prior to Cycle 1 Day 1. Prophylactic use of low-molecular weight heparin (LMWH)
             (i.e., enoxaparin 40 mg/day) is allowed. However, the use of direct oral anticoagulant
             therapies such as dabigatran (Pradaxa®) and rivaroxaban (Xarelto®) is not recommended
             due to bleeding risk.

          -  History of abdominal or tracheoesophageal fistula, GI perforation, or intra-abdominal
             abscess within 6 months prior to Cycle 1 Day 1.

          -  Evidence of abdominal free air that is not explained by paracentesis or recent
             surgical procedure.

          -  Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture.

          -  Major surgical procedure within 4 weeks prior to Cycle 1 Day 1 or anticipation of need
             for a major surgical procedure during the study.

          -  History of intra-abdominal inflammatory process within 6 months prior to Cycle 1 Day
             1, including, but not limited to, peptic ulcer disease, diverticulitis, or colitis.

          -  Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID).

          -  Pregnant or breastfeeding, or intending to become pregnant during the study or within
             5 months after the last dose of atezolizumab and 6 months after the last dose of
             bevacizumab. Women of childbearing potential must have a negative serum pregnancy test
             result within 14 days prior to initiation of study treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate in PD-L1 negative melanoma
Time Frame:5 Years
Safety Issue:
Description:The primary endpoint for this study is overall response rate in PDL1 negative melanoma to combination anti-PD-L1 therapy and anti-VEGF therapy by RECIST criteria. The proportion of patients with complete response or partial response as best response to therapy will be summarized and presented with a two-sided, 90% Wald confidence interval.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:start of treatment and death from any cause up to 5 years
Safety Issue:
Description:Time from start of treatment to death
Measure:Time to tumor progression
Time Frame:up to 5 years
Safety Issue:
Description:Time to tumor progression (TTP) is the time interval between the dates of the start of trial treatment and first documentation of progressive disease
Measure:Duration of response
Time Frame:patients with objective response (confirmed CR or PR as best overall response) as the interval between dates of first documentation of objective response and first documentation of progressive disease up to 5 years
Safety Issue:
Description:The time-to-event endpoints will each be summarized using the method of KaplanMeier Point estimates for each endpoint will be presented with 90% confidence intervals derived using log(-log(endpoint)) methodology.
Measure:Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE 5.
Time Frame:initiation of study treatment, during study treatment, and 30 days after the last dose of study treatment or study discontinuation/termination, whichever occurs first up to 5 years
Safety Issue:
Description:Adverse events
Measure:Change tumor-infiltrating lymphocytes (TILs)
Time Frame:baseline and progression/treatment discontinuation up to 5 years
Safety Issue:
Description:Pre-treatment percentages of stromal infiltrating lymphocytes will be summarized descriptively for the two response groups and compared using Wilcoxon rank-sum tests. Changes in TILs between baseline and progression/treatment discontinuation will be calculated (post-pre) for each patient and summarized descriptivelyChanges in TILs between baseline and progression/treatment discontinuation will be calculated (post-pre) for each patient and summarized descriptively

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Elizabeth Buchbinder

Trial Keywords

  • Metastatic stage III cutaneous melanoma
  • Metastatic stage IV cutaneous melanoma
  • Unresectable stage III cutaneous melanoma
  • Unresectable stage IV cutaneous melanoma

Last Updated

April 20, 2020