A Study of CPI-0209 in Patients With Advanced Solid Tumors and Lymphomas

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.

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