Study Description
First-in-human, open-label, sequential dose escalation and expansion study of CPI-0209 in patients with advanced solid tumors and lymphomas. CPI-0209 is a small molecule inhibitor of EZH2. Emerging evidence suggests that EZH2 is overexpressed in many cancer types and has a pivotal role in disease progression. This is a Phase 1/2, open-label, multi-center, FIH study designed to evaluate the safety and tolerability and preliminary clinical activity of CPI-0209, an EZH2/1 inhibitor as monotherapy in patients with advanced solid tumors and lymphomas. Phase 1 is composed of a CPI-0209 Dose Escalation period in patients with advanced tumors and aims to determine maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of CPI-0209 as monotherapy in patients with advanced tumors.
Phase 2 is planned to evaluate safety and tolerability and antitumor activity of CPI-0209 in six disease-specific cohorts (M1 to M6). Patients in Cohorts M1, M2, M3, M5, and M6 will be enrolled at 10 to 29 patients per cohort, using a Simon 2-stage design. Cohort M4 will enroll up to 20 patients with lymphoma in a single-stage. The primary aim of Phase 2 part of the study is to evaluate the antitumor activity of CPI-0209, and characterize the safety and tolerability of CPI-0209 as monotherapy in patients with selected tumors.
In Phase 2, two additional doses are planned to be evaluated in cohorts M2 and M3 in 2 stages: Stage 2a and Stage 2b. In Stage 2a approximately 20 patients will be enrolled per cohort and will be randomized 1:1 to receive 2 prespecified dose levels of CPI-0209 once daily. When protocol criteria for initiating Stage 2b will be fulfilled after completion of Stage 2a, then Stage 2b will be opened for enrolment of additional 10 patients in one or both dose arms in each of the two cohorts. Thus, up to 40 patients per cohort (M2 and M3) could be enrolled.
Interventions
CPI-0209
Eligibility Criteria
Inclusion Criteria:
Phase 1
Eligible Phase 1 patients are adults who have a confirmed locally advanced or metastatic tumors (solid tumors or lymphoma) that have relapsed following standard therapy or progressed through standard therapy or who have a disease for which no standard effective therapy exists.
Phase 2:
* Life expectancy of ≥ 12 weeks
* ECOG 0-1
* Adequate bone marrow function
* Adequate renal function
* Adequate liver function
For Cohort M1, the following criteria should be considered:
* Histologically confirmed locally advanced unresectable or metastatic urothelial carcinoma with predominant urothelial histology
* • Histologically confirmed metastatic solid tumor (except ovarian clear cell cancer, endometrial cancer, and pleural or peritoneal mesothelioma)
* Known ARID1A mutation (NGS testing)
* Disease progression during or following prior chemotherapy approved therapies or for which no standard therapy exists
* Measurable disease per RECIST 1.1
For Cohort M2, the following criteria should be considered:
* Histologically confirmed advanced ovarian clear cell carcinoma
* Known ARID1A mutation (by NGS testing)
* Received at least 1 line of platinum-based chemotherapy and must have received bevacizumab as part of any line of treatments unless contraindicated or locally not approved or locally not accessible
* Measurable disease per RECIST 1.1
* Patient must have disease progression after previously receiving effective and available standard of care treatment for clear cell ovarian cancer per local clinical practice
For Cohort M3, the following criteria should be considered:
* Histologically or cytologically confirmed recurrent, metastatic, or unresectable endometrial carcinoma
* Known ARID1A mutation (by NGS testing)
* Received at least 1 line of platinum-based regimen in recurrent/metastatic setting
* Documented microsatellite instability (MSI)-high or deficient mismatch repair (dMMR) or patients who have non-dMMR/microsatellite stable tumors should have received an anti-PD-1 or anti-PD-L1 agent alone or in combination with the approved agents as applicable, as part of their prior treatments unless considered not eligible, contraindicated or if not locally approved
* Brachytherapy is allowed if completed \>12 weeks before the first dose of study drug
* Measurable disease per RECIST 1.1
* Patients must have previously received effective and available standard of care treatment options for endometrial cancer per local clinical practice unless these are contraindicated
For Cohort M4, the following criteria should be considered:
* PTCL or DLBCL with the following criteria:
* PTCL
* Documented refractory, relapsed, or progressive disease after at least 1 prior line of systemic therapy. Refractory is defined as:
* Failure to achieve CR after first-line therapy
* Failure to reach at least PR after second-line therapy or beyond
* Must have at least 1 prior line of systemic therapy for PTCL.
* Participants must be considered hematopoietic cell transplantation (HCT) ineligible during screening due to disease status (active disease), comorbidities, or other factors; the reason for HCT ineligibility must be clearly documented.
* In the PTCL cohort, participants with anaplastic large cell lymphoma (ALCL) must have prior brentuximab vedotin treatment.
* DLBCL:
* Relapsed or refractory disease following 2 or more prior lines of standard therapy.
* Not considered candidates to receive CAR-T or autologous hematopoietic stem cell transplant (ASCT) as assessed by the treating investigator for reasons such as age, underlying comorbidities, performance status, or due to disease progression after previously received ASCT or CAR-T. The reason for transplant ineligibility must be clearly documented.
* For patients who underwent past ASCT or CAR-T treatment, at least 90 days must have elapsed since the start of the procedure. For all other patients, at least 8 weeks must have elapsed since their most recent systemic anti-DLBCL therapy
For Cohort M5, the following criteria should be considered:
* Pleural or peritoneal relapsed/refractory mesothelioma
* Must have progressed on or after at least 1 prior line of active therapy
* Measurable disease per modified RECIST 1.1 for pleural mesothelioma or by RECIST 1.1 for peritoneal mesothelioma
* Known BAP1 loss per immunohistochemistry (IHC) or NGS
For Cohort M6, the following criteria should be considered:
* Have measurable soft-tissue disease
* Documented metastatic disease
* Disease progression while on prior therapies
* Baseline testosterone ≤50 ng/dL (≤2.0 nM) and surgical or ongoing medical castration must be maintained throughout the duration of the study
Exclusion Criteria
Medical Conditions
* Previous solid organ or allogeneic hematopoietic cell transplant (HCT)
* Known symptomatic untreated brain metastases
* Clinically significant cardiovascular disease
* Major surgery within 4 weeks before starting study drug or not recovered from any effects of prior major surgery
* Gastrointestinal disorders or any other condition that may significantly interfere with absorption of the study medication by Investigator's assessment.
* Uncontrolled active infection requiring intravenous antibiotic, antiviral, or antifungal medications within 14 days before the first dose of study drug. Infections (eg, urinary tract infection) controlled on concurrent antimicrobial agents and antimicrobial prophylaxis per institutional guidelines are acceptable.
* Suspected pneumonitis or interstitial lung disease or a history of pneumonitis or interstitial lung disease.
* Have a history of a concurrent or second malignancy. Patients with a history of T-cell lymphoblastic lymphoma or T-Cell lymphoblastic leukemia are not eligible.
* Have current known active or chronic infection with HIV, hepatitis B, or hepatitis C. Screening of patients with serologic testing for these viruses is not required
* Clinically active or symptomatic viral hepatitis or chronic liver disease.
* Unstable or severe uncontrolled medical condition or any important medical or psychiatric illness or abnormal laboratory finding
* Previous solid organ or allogeneic hematopoietic cell transplant HCT.
Prior/Concomitant Therapy:
* Prior anticancer treatment:
* Prior systemic anticancer treatment with chemotherapy, targeted therapy, small molecule, antibody, or investigational anticancer therapy (includes prior PD-1 or PD-L1 therapy), or other anticancer therapeutic with the exception of gonadotropin releasing hormone analogues, within 4 weeks (or 5 half-lives), whichever is shorter, before the first dose of study drug (6 weeks washout for nitrosoureas or mitomycin C).
* Previous treatment with an EZH2 inhibitor
* Prior radiation therapy within 4 weeks before first dose of study drug
* Prior stereotactic body radiation therapy within 2 weeks before first dose of study drug
* Prior chemoembolization or radioembolization within 4 weeks before first dose of study drug.
* Concomitant medication(s) or food or beverage that are strong CYP3A inducers or inhibitors within 7 days prior to the first dose of study drug.
Other Exclusions
• Breastfeeding or pregnant woman or expecting to conceive or father children within the projected duration of the trial, starting with the Screening visit through 183 days after the last dose of study drug.
Cohort M6 (mCRPC) only
* Bone-only disease without nodal disease and no evidence of visceral spread
* Structurally unstable bone lesions concerning for impending fracture
* Herbal products that may decrease prostate-specific antigen within 4 weeks prior to Day 1 of treatment and while on study
* Treatment for prostate cancer (First generation androgen receptor antagonists within 4 weeks; 5α-reductase inhibitors, ketoconazole, estrogens, or progesterones within 2 weeks)
* Planned palliative procedures such as radiation therapy or surgery
Oscar Lambret Center
Recruiting
Lille,59020,France
Cyril Abdeddaim
Hospital North
Recruiting
Nantes,44093,France
Thomas Gastinne
Thomas Gastinne, MD
Strasbourg Europe Institut of Cancerology
Recruiting
Strasbourg,23025,France
Lauriane Eberst
Gustave Roussy
Recruiting
Villejuif,94805,France
Vincent Ribrag, MD
Leon Berard Center
Recruiting
Lyon,69373,France
Mehdi Brahmi
Bergonie Institute
Recruiting
Bordeaux,33000,France
Antoine Italiano
Gruppo Humanitas - Humanitas Research Hospital - Cancer Center
Recruiting
Milan,20089,Italy
Carmelo Carlo-Stella
University Polyclinic Foundation "Agostino Gemelli" - IRCCS
Recruiting
Rome,00168,Italy
Vanda Salutari
National Cancer Institute, IRCCS
Recruiting
Milan,20133,Italy
Fedelica Mogavero
Mara Mantiero
European Institute of Oncology (IEO), IRCCS
Recruiting
Milan,20141,Italy
Nicoleta Colombo
Irccs University Hospital of Bologna
Recruiting
Bologna,40138,Italy
Pier Luigi Zinzani, MD
Asan Medical Center
Recruiting
Seoul,05505,Korea, Republic of
Hur Soo Yung
Gachon University Gil Medical Center
Recruiting
Incheon,21565,Korea, Republic of
Lee Kwang-Beom
Gangnam Severance Hospital
Recruiting
Seoul,Korea, Republic of
Jae-Hoon Kim
Seoul National University Hospital
Recruiting
Seoul,03080,Korea, Republic of
Kim Jae-Weon
Keimyung University - Dongsan Medical Center
Recruiting
Daegu,42601,Korea, Republic of
Chi Chi-Heum
Severance Hospital, Yonsei University Health System
Recruiting
Seoul,03722,Korea, Republic of
Lee Jung-Yun
National Cancer Center
Recruiting
Gyeonggi-do,10408,Korea, Republic of
Lim Myong Cheol
Polish Mother's Memorial Hospital-Research Institute
Recruiting
Lodz,Poland
Jan Walewski, MD
Marek Kotlarski, MD
Ewa Kalinka
University Teaching Hospital in Poznan, Department of Gynecologic Oncology
Recruiting
Poznan,60-569,Poland
Radoslaw Madry
University Teaching Centre, Early Clinical Trials Unit
Recruiting
Gdansk,80-214,Poland
Rafal Dziadziuszko
University Hospital Vall d'Hebron
Recruiting
Barcelona,Spain
Ana Oaknin
Alejandro Falcon Gonzalez
Valentina Boni
Maria Pilar Barretina Ginesta
Jesus Alarcon
Antonio Gonzalez Martin
Ignacio Romero Noguera
Teresa Curiel Garcia
Ana Landa Magdalena
Luis Manso Sanchez
University Clinical Hospital of Salamanca
Recruiting
Salamanca,Castilla Y Leon,37007,Spain
Martin Garcia-Sancho, MD, PhD
Royal United Hospital
Recruiting
Bath,United Kingdom
Emma Cattell
Harriet Walter, MD
Rebecca Bowen
Susana Banerjee
Imperial College Healthcare NHS Trust
Recruiting
London,Sw7 2az,United Kingdom
Jonathan Krell
Dana Farber Cancer Institute
Recruiting
Boston,Massachusetts,02215,United States
Alok Tewari, MD
Swedish Cancer Institute
Recruiting
Seattle,Washington,98104,United States
Charles Drescher, MD
Winship Cancer Institute of Emory University
Recruiting
Atlanta,Georgia,30322,United States
R. Donald Harvey, MD
NYU Langone Medical Center - Laura and Isaac Perlmutter Cancer Center
Recruiting
New York,New York,10016,United States
Salman Punekar, MD
South Texas Accelerated Research Therapeutics (Start) - Midwest Location
Recruiting
Grand Rapids,Michigan,49546,United States
Nehal Lakhani, MD
University of Chicago Medical Center
Recruiting
Chicago,Illinois,60637,United States
Hedy Kindler, MD
South Texas Accelerated Research Therapeutics
Recruiting
San Antonio,Texas,78229,United States
Drew Rasco, MD
Fred Hutchinson Cancer
Recruiting
Seattle,Washington,98109-1023,United States
Kalyan Banda, MD
Massachusetts General Hospital
Recruiting
Boston,Massachusetts,02114,United States
Ryan Sullivan, MD
Hackensack University Medical Center
Recruiting
Hackensack,New Jersey,07601,United States
Martin Gutierrez, MD
University of Virginia Health System
Recruiting
Charlottesville,Virginia,22903,United States
Linda Duska, MD
Worldwide Contacts
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