Clinical Trials /

Study of Durvalumab and Guadecitabine in Advanced Kidney Cancer

NCT03308396

Description:

This is a single arm, multi-centre (via Big Ten Cancer Research Consortium) phase Ib/II study of patients treated with durvalumab 1500 mg IV q 4 weeks in combination with guadecitabine at the recommended phase 2 dose subcutaneously for 5 consecutive days. Eligible patients will have metastatic RCC with a clear cell component, ECOG performance status of 0-1, have received 0-1 prior therapy but no prior anti-PD-1/PD-L1/CTLA4 (Cohort 1, 36 subjects). Study treatment could potentially continue for up to 13 cycles (52 weeks).

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Durvalumab and Guadecitabine in Advanced Kidney Cancer
  • Official Title: Single Arm Phase Ib/II Study of Durvalumab and Guadecitabine in Advanced Kidney Cancer: Big Ten Cancer Research Consortium BTCRC-GU16-043

Clinical Trial IDs

  • ORG STUDY ID: BTCRC-GU16-043
  • NCT ID: NCT03308396

Conditions

  • Advanced Kidney Cancer
  • Kidney Cancer
  • Clear Cell Renal Cell Carcinoma

Interventions

DrugSynonymsArms
GuadecitabineSGI-110Single Arm
DurvalumabMEDI4736Single Arm

Purpose

This is a single arm, multi-centre (via Big Ten Cancer Research Consortium) phase Ib/II study of patients treated with durvalumab 1500 mg IV q 4 weeks in combination with guadecitabine at the recommended phase 2 dose subcutaneously for 5 consecutive days. Eligible patients will have metastatic RCC with a clear cell component, ECOG performance status of 0-1, have received 0-1 prior therapy but no prior anti-PD-1/PD-L1/CTLA4 (Cohort 1, 36 subjects). Study treatment could potentially continue for up to 13 cycles (52 weeks).

Detailed Description

      A total of up to 58 subjects will be enrolled on both phases.

      Phase Ib: 6-12 subjects; enrolled into either Cohort 1 or 2. Phase II: 46 subjects; enrolled
      into either Cohort 1 or 2.

      Cohort 1 (36 subjects): received 0-1 prior therapy and no prior anti-PD-1/PD-L1/CTLA4.

      Cohort 2 (16 subjects): received up to 2 prior therapies, one of which must include an
      anti-PD-1/PD-L1 therapy to which they did not respond. Only one prior anti-PD-1/PD-L1 therapy
      is allowed.

      Patients from Phase Ib treated at the eventual phase II dose will be combined with patients
      in Phase II in the efficacy analysis.

        -  Therapy will start with guadecitabine on days 1-5 of a 28-day cycle. Guadecitabine will
           be dosed subcutaneously on days 1-5 at either dose level 0 (60 mg/m2) or dose level -1
           (45 mg/m2), based on the recommended phase II dose.

        -  Durvalumab will be started on day 8 of the 28-day cycle. Durvalumab will be administered
           intravenously at a flat dose of 1500mg every 28 days.

        -  Study treatment may continue for up to 13 cycles (52 weeks) in the absence of confirmed
           progression, intolerable toxicity, or withdrawal of consent.

      Phase Ib Treatment Plan

        -  Dose limiting toxicities (DLTs) will be evaluated within the first cycle (i.e., within
           the first 28 days).

        -  Six patients will be enrolled at dose level 0. If 2 or fewer patients experience a dose
           limiting toxicity, the study will continue to the phase II portion at dose level 0.

        -  Alternately, if 3 or more patients have a dose limiting toxicity at dose level 0, 6
           patients will be accrued at the lower dose (dose -1). If 2 or fewer patients experience
           a dose limiting toxicity, the study will continue to phase II at dose level -1.

        -  If 3 or more subjects experience a dose limiting toxicity at dose level -1, the
           treatment will be considered unsafe and the trial will be stopped. In this case,
           durvalumab and guadecitabine will be permanently discontinued and the subjects followed
           per protocol.
    

Trial Arms

NameTypeDescriptionInterventions
Single ArmExperimentalThis is a non-randomized, single arm, open label Phase Ib/II study. Phase Ib: Days 1-5 Guadecitabine: Dose 0: 60 mg/m^2 Dose -1: 45 mg/m^2 Phase II: Days 1-5 Guadecitabine (at Ph II dose) Day 8 Durvalumab (1500 mg IV) Day 8 Durvalumab (1500 mg IV)
  • Guadecitabine
  • Durvalumab

Eligibility Criteria

        Inclusion Criteria:

        Subject must meet all of the following applicable inclusion criteria to participate in this
        study:

          -  Written informed consent and HIPAA authorization for release of personal health
             information.

          -  ECOG Performance Status 0-1 within 28 days prior to registration.

          -  Histological diagnosis of clear cell renal cell carcinoma (pure or mixed) with
             radiologic or histologic evidence of metastatic disease.

          -  At least 1 lesion, not previously irradiated that can be accurately measured at
             baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have a
             short axis ≥ 15mm) with a computed tomography (CT) or magnetic resonance imaging (MRI)
             and that is suitable for accurate repeated measurements as per Response Evaluation
             Criteria in Solid Tumors, version 1.1 (RECIST 1.1) guidelines.

          -  For cohort 1, subjects may have received up to 1 and no more than 1 prior line of
             systemic therapy (not counting any neoadjuvant/adjuvant therapy) including anti-VEGF,
             VEGFR inhibitor, MET inhibitor or mTOR inhibitor for metastatic disease. They cannot
             have received any prior anti-PD-1/PD-L1/CTLA4 therapy including durvalumab.

          -  For cohort 2, subjects may have received up to 2 prior systemic therapies which should
             include 1 (and only 1) prior anti-PD-1/PD-L1 therapy but did not have an objective
             response to the prior anti-PD-1/Pd-L1 therapy. The treating investigator must document
             that the patient did not have an objective response to prior anti-PD-1/PD-L1 therapy.
             They may have received prior anti-CTLA4 therapy.

          -  Subjects may not have had radiotherapy treatment to more than 30% of the bone marrow
             or with a wide field of radiation within 4 weeks of the first dose of study drug.

          -  Prior cancer treatment must be completed at least 14 days prior to study registration
             and the subject must have recovered from all reversible acute toxic effects of the
             regimen (other than alopecia) to ≤Grade 1 or baseline.

          -  Demonstrate adequate organ function as defined in the table below; all screening labs
             to be obtained within 28 days prior to registration:

        Hematological:

          -  White blood cell (WBC) ≥ 3 K/mm^3

          -  Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm^3

          -  Hemoglobin (Hgb) ≥ 9 g/dL

          -  Platelets (Plt) ≥ 100,000/mm^3

        Renal:

          -  Calculated creatinine clearance ≥ 40 cc/min using the Cockcroft-Gault formula

        Hepatic:

          -  Bilirubin ≤ 1.5 × upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) ≤ 2.5 × ULN

          -  Alanine aminotransferase (ALT) ≤ 2.5 × ULN

               -  Females of childbearing potential must have a negative serum pregnancy test
                  within 28 days prior to registration.

               -  Females of childbearing potential and males must be willing to abstain from
                  heterosexual activity or to use at least 1 highly effective methods of
                  contraception from the time of informed consent until 30 days after treatment
                  discontinuation. The two contraception methods can be comprised of two barrier
                  methods, or a barrier method plus a hormonal method.

               -  Life expectancy ≥ 12 weeks (in the opinion of the Investigator)

               -  Body weight >30kg

               -  Subject is willing and able to comply with the protocol for the duration of the
                  study including undergoing treatment and scheduled visits and examinations
                  including follow up.

        Exclusion Criteria:

        Subjects meeting any of the criteria below may not participate in the study:

          -  Active infection requiring systemic therapy.

          -  Brain metastases or spinal cord compression. Patients with suspected brain metastases
             at screening should have an MRI (preferred) or CT each preferably with IV contrast of
             the brain prior to study entry. Patients whose brain metastases have been treated may
             be considered if they have completed their treatment for brain metastasis at least 4
             weeks prior to study registration provided they show radiographic stability (defined
             as 1 brain image, obtained after treatment to the brain metastases). In addition, any
             neurologic symptoms that developed either as a result of the brain metastases or their
             treatment must have resolved or be stable without the use of steroids for at least 14
             days prior to the start of treatment.

          -  Pregnant or breastfeeding

          -  History of another primary malignancy except for:

               -  Malignancy treated with curative intent and with no known active disease ≥5 years
                  before the first dose of IP and of low potential risk for recurrence.

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease.

               -  Adequately treated carcinoma in situ without evidence of disease.

          -  Treatment with any investigational drug within 14 days prior to study registration.

          -  Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
             the exception of diverticulosis], celiac disease, irritable bowel disease, or other
             serious gastrointestinal chronic conditions associated with diarrhea, systemic lupus
             erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with
             polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc])
             within the last 3 years prior to study registration. The following are exceptions to
             this criterion: The following are exceptions to this criterion:

               -  Subjects with vitiligo or alopecia.

               -  Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
                  replacement.

               -  Any chronic skin condition that does not require systemic therapy.

               -  Subjects without active disease in the last 5 years may be included but only
                  after consultation with the study physician.

               -  Subjects with celiac disease controlled by diet alone.

          -  Current or prior use of immunosuppressive medication within 28 days before the first
             dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or
             systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
             prednisone, or an equivalent corticosteroid. The following are exceptions to this
             criterion:

               -  Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra
                  articular injection).

               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent.

               -  Steroids as premedication for hypersensitivity reactions (eg, CT scan
                  premedication).

          -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca/
             MedImmune staff and/or staff at the study site).

          -  Concurrent enrollment in another clinical study, unless it is an observational
             (non-interventional) clinical study or during the follow-up period of an
             interventional study.

          -  Any concurrent chemotherapy, biologic or hormonal therapy for cancer treatment.
             Concurrent use of hormonal therapy for non-cancer-related conditions (e.g. hormone
             replacement therapy) is acceptable. Note: Local treatment of isolated lesions,
             excluding target lesions, for palliative intent is acceptable (e.g., local surgery or
             radiotherapy).

          -  Major surgical procedure (as defined by the Investigator) within 28 days prior to
             study registration. Note: local surgery of isolated lesions for palliative intent is
             acceptable.

          -  History of allogenic organ transplantation that requires use of immunosuppressive
             agents.

          -  Uncontrolled intercurrent illness including but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric
             illness/social situations that would limit compliance with study requirement,
             substantially increase risk of incurring AEs or compromise the ability of the patient
             to give written informed consent.

          -  History of leptomeningeal carcinomatosis.

          -  Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings), hepatitis B (known positive
             HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus
             (positive HIV 1/2 antibodies). Subjects with a past or resolved HBV infection (defined
             as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are
             eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if
             polymerase chain reaction is negative for HCV RNA.

          -  Receipt of live attenuated vaccine within 30 days prior to the first dose of study
             drug. Note: patients, if enrolled, should not receive live vaccine during the study
             and up to 30 days after the last dose of study drug.

          -  Female patients who are pregnant or breastfeeding or male or female patients of
             reproductive potential who are not willing to employ effective birth control from
             screening to 90 days after the last dose of study drug.

          -  Known allergy or hypersensitivity to study drugs or other humanized monoclonal
             antibodies.

          -  Patient ≤30kg in weight.

          -  Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3
             electrocardiograms (ECGs) using Fridericia's Correction.

          -  Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
             criteria:

               -  Subjects with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
                  consultation with the Study Physician.

               -  Subjects with irreversible toxicity not reasonably expected to be exacerbated by
                  treatment with durvalumab may be included only after consultation with the Study
                  Physician.

          -  Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required
             steroid treatment, or any evidence of clinically active interstitial lung disease.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase Ib: Dose limiting toxicities will be assessed to determine if the trial is stopped before the Phase II portion.
Time Frame:28 days/First cycle
Safety Issue:
Description:Number of patients with dose-limiting toxicity (DLT) of the combination of durvalumab and guadecitabine

Secondary Outcome Measures

Measure:Phase II: Overall Survival (OS)
Time Frame:2 years
Safety Issue:
Description:will be reported with 95% confidence intervals from the Kaplan-Meier estimates.
Measure:Phase II: Duration of Response (DoR)
Time Frame:2 years
Safety Issue:
Description:will be assessed using Kaplan-Meier estimates including the 95% confidence band separately for cohort 1 and for cohort 2.
Measure:Phase II: Progression-free survival (PFS)
Time Frame:2 years
Safety Issue:
Description:will be assessed using Kaplan-Meier estimates including the 95% confidence band separately for cohort 1 and for cohort 2.
Measure:Phase II: Clinical benefit rate (CBR)
Time Frame:2 years
Safety Issue:
Description:reported as binomial proportions and corresponding 95% binomial confidence intervals separately for cohort 1 and cohort 2
Measure:Phase II: Complete response (CR) proportion
Time Frame:2 years
Safety Issue:
Description:reported as binomial proportions and corresponding 95% binomial confidence intervals separately for cohort 1 and cohort 2
Measure:Phase II: Objective Response Rate (ORR)
Time Frame:2 years
Safety Issue:
Description:reported as binomial proportions and corresponding 95% binomial confidence intervals separately for cohort 1 and cohort 2
Measure:Phase II: Assess Adverse Events
Time Frame:2 years
Safety Issue:
Description:by CTCAE ver 4 including events of special interest such as immune mediated toxicities

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Ajjai Alva, MD

Trial Keywords

  • Durvalumab
  • Guadecitabine

Last Updated