Clinical Trials /

DS3201 and Ipilimumab for the Treatment of Metastatic Prostate, Urothelial and Renal Cell Cancers

NCT04388852

Description:

This phase Ib trial studies the side effects and best dose of DS3201 when given together with and ipilimumab for the treatment of patients with prostate, urothelial, or renal cell cancer that has spread to other places in the body (metastatic). DS3201 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving DS3201 and ipilimumab may help to control the disease.

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

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: DS3201 and Ipilimumab for the Treatment of Metastatic Prostate, Urothelial and Renal Cell Cancers
  • Official Title: DS3201 With Ipilimumab in Patients With Metastatic Aggressive Variant Prostate (AVPC), Urothelial (UC), and Renal Cell (RCC) Carcinomas

Clinical Trial IDs

  • ORG STUDY ID: 2019-0967
  • SECONDARY ID: NCI-2020-02916
  • SECONDARY ID: 2019-0967
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04388852

Conditions

  • Aggressive Variant Prostate Carcinoma
  • Castration-Resistant Prostate Carcinoma
  • Metastatic Clear Cell Renal Cell Carcinoma
  • Metastatic Malignant Solid Neoplasm
  • Metastatic Prostate Carcinoma
  • Metastatic Urothelial Carcinoma
  • Stage IV Prostate Cancer AJCC v8
  • Stage IV Renal Cell Cancer AJCC v8
  • Stage IVA Prostate Cancer AJCC v8
  • Stage IVB Prostate Cancer AJCC v8

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTreatment (valemetostat, ipilimumab)
ValemetostatDS 3201, DS-3201, DS3201Treatment (valemetostat, ipilimumab)

Purpose

This phase Ib trial studies the side effects and best dose of DS3201 when given together with and ipilimumab for the treatment of patients with prostate, urothelial, or renal cell cancer that has spread to other places in the body (metastatic). DS3201 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving DS3201 and ipilimumab may help to control the disease.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) and confirm the safety and tolerability of
      valemetostat (DS3201) given in combination with ipilimumab in patients with metastatic
      aggressive variant prostate cancers (AVPC), urothelial carcinomas (UC) and renal clear cell
      carcinomas (RCC).

      II. To screen for associations between changes in the tumor microenvironment and clinical
      outcomes.

      SECONDARY OBJECTIVES:

      I. To assess the immunologic and molecular effects on tissue samples of participants treated
      with DS3201 in combination with ipilimumab in patients with metastatic AVPC, UC and RCC.

      II. To estimate the time to treatment failure (TTF) of patients with metastatic AVPC, UC and
      RCC treated with DS3201 in combination with ipilimumab.

      III. To estimate the overall response rate (ORR) of patients with metastatic AVPC, UC and RCC
      treated with DS3201 in combination with ipilimumab (in patients with AVPC ORR will be
      reported separately for prostate specific antigen [PSA], circulating tumor cells [CTC] and
      measurable and non-measurable disease by Response Evaluation Criteria in Solid Tumors
      [RECIST] 1.1).

      OUTLINE: This is a dose-escalation study of valemetostat.

      Patients receive valemetostat orally (PO) once daily (QD) on days 1-21 and ipilimumab
      intravenously (IV) over 90 minutes on day 1 of cycles 1 and 3. Cycles repeat every 21 days in
      the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up 30 and 60 days after the last
      valemetostat dose and/or 100 days after the last ipilimumab dose and then every 6 months
      thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (valemetostat, ipilimumab)ExperimentalPatients receive valemetostat PO QD on days 1-21 and ipilimumab IV over 90 minutes on day 1 of cycles 1 and 3. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Valemetostat

Eligibility Criteria

        Inclusion Criteria:

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Histologically or cytologically confirmed prostate carcinomas, urothelial carcinomas
             and clear cell renal carcinomas. For patients with prostate carcinomas, variant
             histologies, such as small cell or neuroendocrine carcinomas are permitted

          -  Evidence of metastatic disease by conventional imaging studies (computed tomography
             [CT], magnetic resonance imaging [MRI] and/or bone scan). Patients with locally
             advanced disease that is not amenable to locoregional therapies such as surgery or
             radiation, are considered metastatic and eligible to participate

          -  Patients with prostate carcinomas must have castration resistant disease, i.e.
             evidence of disease progression while having castrate levels of testosterone (=< 50
             ng/dL or =< 2.0 nM) or an unsatisfactory response to >= 1 month of castration, as
             defined by lack of symptom control and/or serum tumor marker response of < 20%
             (confirmed by a second value drawn on a different day). Exception: patients with small
             cell carcinoma histology are not required to have progressed during prior androgen
             deprivation therapy. However, all patients with prostate cancer (including those with
             small cell carcinomas) are required to maintain castrate levels of testosterone
             throughout the duration of the study

          -  Patients with prostate carcinomas must also display the AVPC molecular signature (i.e.
             known loss or mutation [by Clinical Laboratory Improvement Act (CLIA) certified
             molecular testing by immunohistochemistry (IHC) and/or deoxyribonucleic acid (DNA)
             sequencing in solid tumor samples, and/or in circulating tumor DNA]) in at least 2 of
             the following: Tp53, RB1 and PTEN

          -  Patients with renal cell carcinomas (RCC) must have had progressive disease during or
             after treatment with at least one anti-angiogenic agent and one PD-1 or PD-L1
             inhibitor

          -  Patients with urothelial carcinomas (UC) must have had progressive disease during or
             after treatment with at least one anti-PD1 or PD-L1 inhibitor and must have previously
             been treated with platinum-based chemotherapy or not be eligible for platinum based
             chemotherapy

          -  Patients with AVPC are allowed to have received prior treatment with a PD-1 or PD-L1
             inhibitor, but are not required to have had it

          -  Evidence of disease progression as defined by new or increasing measurable and/or
             non-measurable disease as per RECIST

          -  For patients with AVPC, rising PSA values (a minimum of 2 rising values over 3
             measurements obtained a minimum of 7 days apart with the last result being >= 1.0
             ng/mL, as per Prostate Cancer Working Group 3 [PCWG3]) can also be considered evidence
             of progressive disease for eligibility as long as the molecular AVPC criteria are also
             met

          -  If patient has known brain metastases, must have stable neurologic status following
             local therapy for at least 4 weeks without the use of steroids or on stable or
             decreasing dose of =< 10 mg daily prednisone (or equivalent), and must be without
             neurologic dysfunction that would confound the evaluation of neurologic and other
             adverse events (AEs)

          -  Recovery from recent surgery, radiotherapy, chemotherapy or any other anti-cancer
             therapy to baseline or =< grade 1 (other than alopecia). Other low grade toxicities
             (e.g. =< grade 2 lymphopenia or hypomagnesemia) may be allowed at the discretion of
             the investigator if considered clinically insignificant

          -  Absolute neutrophil count (ANC) >= 1,500/uL (obtained within 28 days prior to day 1 of
             treatment)

          -  Platelet count >= 100,000/uL (obtained within 28 days prior to day 1 of treatment)

          -  Hemoglobin (Hgb) >= 9 g/dL (obtained within 28 days prior to day 1 of treatment)

          -  Serum creatinine =< 2 x upper limit of normal (ULN) OR creatinine clearance (CrCl) >=
             40 mL/min as estimated by the Cockcroft and Gault formula in subjects with creatinine
             > 2 x ULN (obtained within 28 days prior to day 1 of treatment)

          -  Bilirubin =< 1.5 x ULN unless evidence of Gilbert's disease in which case < 5 x ULN
             (obtained within 28 days prior to day 1 of treatment)

          -  Aspartate aminotransferase (AST) =< 3.0 x ULN without liver metastases; must be =< 5 x
             ULN with liver metastases (obtained within 28 days prior to day 1 of treatment)

          -  Alanine aminotransferase (ALT) =< 3.0 x ULN without liver metastases; must be =< 5 x
             ULN with liver metastases (obtained within 28 days prior to day 1 of treatment)

          -  Serum albumin >= 3 g/dL (obtained within 28 days prior to day 1 of treatment)

          -  Females of childbearing potential (FCBP) must have a negative serum pregnancy test
             within 24 hours prior to start of study drug first dose of ipilimumab. NOTE: Females
             are considered of child bearing potential unless they are surgically sterile (have
             undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are
             postmenopausal (at least 12 consecutive months with no menses without an alternative
             medical cause)

          -  FCBP must be willing to use a highly effective contraceptive method (i.e., achieves a
             failure rate of < 1% per year when used consistently and correctly) from the time of
             informed consent until 3 months after treatment discontinuation. Male subjects must be
             willing to use condoms from the time of informed consent until 3 months after
             treatment discontinuation. For a non-pregnant FCBP partner, contraception
             recommendations should also be considered

          -  Presence of neoplastic disease documented on imaging studies (bone scan, CT and/or MRI
             scans) deemed accessible for serial biopsies (including bone and soft tissues)

          -  Patients must agree to tissue collection for correlative studies (including
             participation in PA13-0291 and PA13-0247 laboratory protocols, and archival tissue
             from a prior biopsy or surgery for prostate cancer where available)

          -  Ability to swallow and retain oral medications

          -  Ability to understand and willingness to sign an Institutional Review Board (IRB)
             approved written informed consent form (ICF) and authorization permitting release of
             personal health information including genetic testing relevant to cancer

          -  Ability to comply with study visit schedule and assessments

        Exclusion Criteria:

          -  Pregnant or lactating

          -  Carcinomatous meningitis

          -  Treatment with any of the following as anti-cancer agents (see Inclusion Criteria #8
             regarding required resolution of treatment-related toxicities):

               -  Prior treatment with an EZH2 inhibitor

               -  PD-1, PD-L1, PD-L2 or CTLA-4 inhibitor (whether commercially available or
                  investigational) within 4 weeks prior to day 1 of treatment

               -  Monoclonal antibody (whether commercially available or investigational) within 4
                  weeks prior to day 1 of treatment

               -  Investigational drug within 2 weeks prior to day 1 of study treatment

               -  Chemotherapy within 2 weeks prior to day 1 of study treatment

               -  Radiation therapy or radionuclide therapy within 2 weeks prior to day 1 of study
                  treatment

          -  Receipt of live virus vaccination within 30 days prior to day 1 of study treatment

          -  Untreated symptomatic spinal cord compressions or brain metastases

          -  Experienced an immune-related adverse event (irAE) that led to permanent
             discontinuation of prior immunotherapy

          -  Experienced a >= grade 3 irAE within the past 16 weeks, any grade 4 life- threatening
             irAE (regardless of duration) or neurologic or ocular AE of any grade while receiving
             prior immunotherapy (NOTE: Patients with endocrine AEs of any grade are permitted to
             enroll if they are stably maintained on appropriate replacement therapy, but must have
             no history of adrenal crisis and be asymptomatic)

          -  Active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes
             mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone
             replacement, psoriasis or eczema not requiring systemic treatment, or conditions not
             expected to recur in the absence of an external trigger are permitted to enroll

          -  Requires chronic systemic treatment with either corticosteroids (> 10 mg daily
             prednisone equivalents) or other immunosuppressive medications. Inhaled, intranasal,
             intra-articular and topical (including ocular) steroids are allowed. Adrenal
             replacement (i.e., physiologic replacement) doses > 10 mg daily prednisone equivalents
             are permitted in the absence of active autoimmune disease

          -  History of interstitial lung disease, idiopathic pulmonary fibrosis or evidence of
             active pneumonitis on screening chest computed tomography (CT) scan

          -  Clinically significant cardiovascular disease including:

               -  Myocardial infarction (MI)/stroke within 6 months prior to day 1 of study
                  treatment

               -  Unstable angina within 3 months prior to day 1 of study treatment

               -  Congestive heart failure (CHF) with New York Heart Association (NYHA) class 3 or
                  4

               -  History of clinically significant ventricular arrhythmias (e.g., ventricular
                  tachycardia, ventricular fibrillation, torsades de pointes)

               -  Uncontrolled hypertension (systolic blood pressure [BP] >= 140 mmHg or diastolic
                  BP >= 90 mmHg). Patients with a history of hypertension are allowed provided
                  blood pressure is controlled by anti-hypertensive treatment

               -  Baseline 12-lead electrocardiogram (ECG) that demonstrates clinically relevant
                  abnormalities that may affect participant safety or interpretation of study
                  results (eg, baseline corrected QT [QTc] interval > 470 msec, complete left
                  bundle branch block [LBBB], signs of an acute myocardial infarction, ST-T
                  interval changes suggestive of active myocardial ischemia, second- or
                  third-degree atrioventricular [AV] block, or serious bradyarrhythmias or
                  tachyarrhythmias). If the baseline uncorrected QT interval is > 470 msec, this
                  interval should be rate-corrected using the Fridericia method and the resulting
                  Fridericia's correction formula (QTcF) should be used for decision making and
                  reporting. If QTc exceeds 470 msec, or QRS exceeds 120 msec, the ECG should be
                  repeated 2 more times and the average of the 3 QTc or QRS values should be used
                  to determine the participant's eligibility. Computer-interpreted ECGs should be
                  over read by a physician experienced in reading ECGs before excluding
                  participants. Cases must be discussed in detail with the principal investigator
                  (PI) to judge eligibility

          -  Known active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
             screening will include hepatitis B surface antigen (HepBsAg) and HCV antibody (Ab). In
             the presence of a positive HCV Ab, HCV ribonucleic acid (RNA) levels will be
             requested. A positive HepBsAg and/or detectable levels of HCV RNA will make patient
             ineligible

          -  Known history of human immunodeficiency virus (HIV) (HIV1/2 antibodies)

          -  Gastrointestinal (GI) disorder that negatively affects absorption (e.g., significant
             intestinal resection resulting in short intestinal syndrome, severe diarrhea,
             requirement for total parenteral nutrition [TPN])

          -  Known additional malignancy that is progressing, requires active treatment or has a >=
             30% probability of recurrence within 24 months. Exceptions include non-melanoma skin
             cancer that has undergone potentially curative therapy, Ta urothelial carcinoma or
             stage 0 chronic lymphocytic leukemia

          -  Any other concurrent severe and/or uncontrolled concomitant medical condition that
             could compromise participation in the study (e.g., known psychiatric disorder,
             clinically significant neurological disorder, active or uncontrolled infection)

          -  Patient unwilling or unable to comply with this study protocol
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 60 days after last valemetostat dose and 100 days after last ipilimumab dose
Safety Issue:
Description:Adverse events will be graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 and tabulated by grade and ETOX status. All adverse events will be presented descriptively by event, grade, and attribution separately by dose level.

Secondary Outcome Measures

Measure:Immunologic and molecular effects
Time Frame:Up to 2 years
Safety Issue:
Description:Descriptive statistics including plots, mean, median and standard deviations will be used to summarize data by dose level and patient disease cohort. Tumor immune cell infiltration and peripheral blood immune populations will be described and graphed over time. Differences in either time point compared to baseline will be compared with a t-test or non-parametric alternative. Cox models will be implemented to explore the relationship of treatment combination, tumor immune infiltration/peripheral blood immune subpopulations, and time to treatment failure.
Measure:Time to treatment failure (TTF)
Time Frame:Up to 2 years
Safety Issue:
Description:Defined as the time interval between the first day of treatment with DS3201 and treatment failure. Median TTF will be reported with a 95% confidence interval using Kaplan-Meier methods. If the median is not reached, then the TTF estimate will be reported with the standard error at a time close to the median follow-up time. The full TTF experience will be presented with a Kaplan-Meier plot overall and by disease cohort.
Measure:Overall response rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description:In patients with renal cell carcinoma and urothelial carcinoma, ORR is defined as the rate of confirmed complete responses + partial responses as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and as assessed by the investigator. In patients with aggressive variant prostate cancer, ORR will be reported separately for prostate specific antigen (>= 50% decline from baseline value), CTC (conversion from unfavorable to favorable counts) and measurable and non-measurable disease (per RECIST 1.1) and as assessed by the investigator. ORR will be reported with a 95% Blythe-Still-Casella exact confidence interval.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

May 12, 2020