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BRIEF TITLE: DS3201 With Ipilimumab in Patients With Metastatic Aggressive Variant Prostate (AVPC), Urothelial (UC), and Renal Cell (RCC) Carcinomas

DS3201 With Ipilimumab in Patients With Metastatic Aggressive Variant Prostate (AVPC), Urothelial (UC), and Renal Cell (RCC) Carcinomas


  • Org Study ID: 2019-0967
  • Secondary ID: NCI-2020-02916,2019-0967
  • NCT ID: NCT04388852
  • NCT Alias:
  • Sponsor: M.D. Anderson Cancer Center - Other
  • Source: M.D. Anderson Cancer Center

Brief Summary

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.

Overal Status Start Date Phase Study Type
Recruiting August 20, 2020 Phase 1 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: Incidence of adverse events

Primary Outcome 1 - Time Frame: Up to 60 days after last valemetostat dose and 100 days after last ipilimumab dose

Primary Outcome 2 - Measure: Maximum tolerated dose

Primary Outcome 2 - Time Frame: Up to 21 days

Condition:

  • 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

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
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Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Official Information

Name: Ana Aparicio

Role: Principal Investigator

Affiliation: M.D. Anderson Cancer Center

Overall Contact

Name: Ana Aparicio

Phone: 713-563-6969

Email: aaparicio@mdanderson.org

Link: MD Anderson Cancer Center Website

Location

Facility Status Contact
M D Anderson Cancer Center
Houston, Texas 77030
United States
Recruiting Ana Aparicio
713-792-2830