NCT02158858 - A Phase 1/2 Study of CPI-0610 With and Without Ruxolitinib in Patients With Hematologic and Myeloproliferative Malignancies | Crick

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Phase I (Dose Escalation) - Inclusion and Exclusion Criteria: 1. Inclusion Criteria (Phase I): * Age: Adults ≥18 years. * Diagnosis: Histologically or cytologically confirmed diagnosis of one of the following hematologic malignancies: * Acute myelogenous leukemia (AML) * Acute lymphocytic leukemia (ALL) * Acute undifferentiated or biphenotypic leukemia * Chronic myeloid leukemia (CML) in blast crisis * Myelodysplastic syndrome (MDS) * Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) * Myelofibrosis (MF) * Performance Status: ECOG ≤2. * Organ Function: * Serum total bilirubin ≤1.5 × ULN * AST/ALT ≤2.5 × ULN (up to 5 × ULN if due to leukemic infiltration) * Serum creatinine ≤2.0 × ULN or CrCl ≥30 mL/min * Hematology (MF only): * Platelet count ≥50 × 10⁹/L and ANC ≥1 × 10⁹/L (MF not on ruxolitinib) * Platelet count ≥75 × 10⁹/L and ANC ≥1 × 10⁹/L (MF on ruxolitinib) * Other: * DIPSS-plus risk category of intermediate-2 or high (MF only) * Serum glucose ≤160 mg/dL (or HbA1C ≤7%) * Fully recovered from major surgery and acute toxic effects of prior therapy * Negative pregnancy test for women of childbearing potential * Agreement to use appropriate contraception * Written informed consent 2. Exclusion Criteria (Phase I): * Untreated newly diagnosed acute leukemia (unless AML with myelodysplasia-related changes and 20-30% blasts) * Relapsed/refractory acute leukemia where further induction chemotherapy is beneficial * Acute leukemia relapse \<6 months after allogeneic SCT * CML in blast crisis treated with only one TKI * Very low/low risk MDS without prior treatment * CNS involvement by leukemia (unless resolved) * Active HIV, Hepatitis B or C infection * GI impairment affecting absorption (unresolved nausea, vomiting, diarrhea \>CTCAE grade 1) * Significant cardiac disease (recent MI/angina, high cTn, QTcF \>470 ms, LVEF \<50%, uncontrolled arrhythmia, etc.) * Severe/uncontrolled comorbidities * Recent systemic anti-cancer therapy (other than hydroxyurea/radiotherapy) \<2 weeks prior * Ongoing or recent JAK inhibitor use (\<2 weeks prior, MF only) * Recent therapeutic antibody (\<4 weeks) or investigational agent (\<2 weeks or \<5 half-lives) * Use of strong CYP450 inhibitors/inducers or drugs with Torsades de Pointes risk * Immunosuppressive treatment that cannot be discontinued * Pregnant/lactating women * Inadequate contraception * Inability/unwillingness to comply with protocol Phase II (Expansion) - Inclusion \& Exclusion Criteria: 1. Inclusion Criteria (Phase II): 1. MF Arms (Prior JAKi, Add-on JAKi, JAKi Naïve) * Age: Adults ≥18 years * Diagnosis: Confirmed primary MF or MF evolved from ET or PV * Risk: DIPSS intermediate-2 or higher * Platelets: * ≥75 × 10⁹/L (Arms 1 \& 2) * ≥100 × 10⁹/L (Arm 3, JAKi naïve) * ANC: ≥1 × 10⁹/L * Spleen Volume: ≥450 cm³ by MRI/CT (non-TD cohorts) OR * Transfusion Dependence: Average ≥2 RBC transfusions/month (total ≥6 in prior 12 weeks) for TD cohorts * Peripheral Blood Blasts: \<10% * Symptoms: At least 2 symptoms measurable (score ≥1 for Arms 1 \& 2; score ≥3 or total ≥10 for Arm 3) using MFSAF v4.0 * Treatment History: * Arm 1 (Prior JAKi): Previously treated with JAKi and intolerant, resistant, refractory, or lost response, or ineligible for JAKi * Arm 2 (Add-on JAKi): On ruxolitinib ≥6 months, stable dose ≥8 weeks, not adequately controlled * Arm 3 (JAKi Naïve): No prior JAKi, eligible for ruxolitinib * Performance Status: ECOG ≤2 * Organ Function: Serum direct bilirubin \<2 × ULN, AST/ALT ≤2.5 × ULN (up to 5 × ULN if due to liver involvement), CrCl ≥45 mL/min * Other: Fully recovered from major surgery/acute toxic effects, effective contraception, written informed consent 2. ET Arm (High-Risk ET) * Age: Adults ≥18 years * Diagnosis: Confirmed ET (WHO 2016 criteria) * High-Risk: At least one of: * Age \>60 years * Platelets \>1500 × 10⁹/L * Prior thrombosis, erythromelalgia, or migraine (disease-related) * Prior hemorrhage related to ET * Diabetes/hypertension requiring therapy \>6 months * Symptoms: ≥2 symptoms with average score ≥3 or total score ≥15 (MPN-SAF) * Platelets: \>600 × 10⁹/L * Resistant/Intolerant to HU: As defined by ELN * Performance Status: ECOG ≤2 * Life Expectancy: \>24 weeks * ANC: ≥1 × 10⁹/L * Organ Function: Serum direct bilirubin \<2 × ULN, AST/ALT ≤2.5 × ULN, CrCl ≥45 mL/min * Other: Fully recovered from major surgery/acute toxic effects, effective contraception, written informed consent 2. Exclusion Criteria (Phase II) * Prior splenectomy (MF non-TD cohorts) * Splenic irradiation within 3 months * Active or chronic HIV, Hepatitis B/C infection * Active clinically significant infection (until recovery ≥2 weeks) * Anemia deemed clinically significant (iron/B12/folate deficiency, hemolytic anemia) * Major bleeding event (≥2 g/dL Hgb drop or ≥2 units transfused in last 6 months) * Liver cirrhosis Child-Pugh B or C * GI impairment affecting absorption (unresolved nausea, vomiting, diarrhea \>CTCAE grade 1) * Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption (Arm 3) * Hypersensitivity to ruxolitinib formulation (Arm 3) * History of PML (Arm 3) * Significant cardiac disease (recent MI/angina, QTcF \>500 ms \[\>450 ms in France/Germany\], uncontrolled arrhythmia, etc.) * Ongoing uncontrolled hypertension * Severe/uncontrolled comorbidities * Systemic anticancer treatment (other than ruxolitinib for Arm 2, HU/ANA up to 24h prior) \<2 weeks or \<5 half-lives prior * Prior treatment with any BET inhibitor * Hematopoietic growth factor or androgenic steroids \<4 weeks prior * Systemic corticosteroids ≥10 mg prednisone equivalent within 4 weeks (exceptions for short courses) * Concurrent/second malignancy (except certain adequately treated cancers) * Pregnant/lactating women, or planning pregnancy within protocol-defined window * Inability/unwillingness to comply with protocol

Outcomes

Primary Outcomes

Phase 1: Frequency of Dose-limiting toxicities (DLTs)

The maximum tolerated dose (MTD) of CPI-0610 and characterize its DLTs in patients with acute leukemia, myelodysplastic syndrome (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and myelofibrosis (MF), when given once daily by mouth for 14 consecutive days followed by a 7-day break.

Time frame: DLTs assessed during Cycle 1 (cycle = 21 days)

Phase 2 (Cohorts 1B, 2B, and Arm 3): Splenic Response Rate by Imaging

Splenic response rate is defined as the proportion of patients who achieve a ≥ 35% reduction from baseline spleen size by imaging (MRI or CT) after 24 weeks of treatment.

Time frame: 24 weeks (Cycle 9, Day 1)

Phase 2 (Cohorts 1A and 2A): Conversion rate from Red Blood Cell (RBC) transfusion dependence (TD) to transfusion independence (TI)

Conversion rate is defined as the proportion of patients who convert from TD to TI, where TD is defined as receiving an average of ≥ 2 units of RBC transfusions per month (total of ≥ 6 RBC transfusions during the 12 weeks) prior to enrollment and TI is defined as absence of RBC transfusions over any consecutive 12 week period

Time frame: 12 consecutive weeks (rolling window, assessed after 24 weeks)

Phase 2 (Arm 4): Complete Hematological Response (CHR) Rate

Complete CHR rate is defined as the proportion of patients who meet the criteria for CHR, as assessed by modified European LeukemiaNet (ELN) criteria: platelet count ≤400 × 10⁹/L, WBC ≤10 × 10⁹/L, laboratory results confirmed after 1 cycle, and normal spleen size by palpation or imaging.

Time frame: Over 2 consecutive cycles (rolling window) (1 cycle = 21 days)

Secondary Outcomes

Phase 1: Incidence rate of adverse events (AEs), serious adverse events (SAEs)

The analysis of adverse events will include categorization by type, frequency, and severity, as graded by the NCI CTCAE version 4.03.

Time frame: Through Phase I completion, an average of 4 years

Phase 2 (All Arms): Incidence rate of adverse events (AEs), serious adverse events (SAEs)

The analysis of adverse events will include categorization by type, frequency, and severity, as graded by the NCI CTCAE version 4.03.

Time frame: Through Phase II completion, an average of 6 years

Phase 2 (All Arms): Change from Baseline in Patient Global Impression of Change (PGIC) at 12 and 24 weeks

The Patient Global Impression of Change (PGIC) is a single-question, patient-reported assessment that asks individuals to rate their overall change in myeloproliferative neoplasm (MPN) symptoms since starting study treatment. The patient select one of seven options, ranging from "Very much improved" to ""Very much worse". No Change from Baseline indicates stable symptoms (no improvement or worsening), negative change from Baseline indicates a reduction in symptom severity (improvement) and positive change from Baseline indicates an increase in symptom severity (worsening).

Time frame: Baseline, 12 weeks (Cycle 5, Day 1), 24 weeks (Cycle 9, Day 1)

Phase 2 (Arms 1, 2 and 3): Change from Baseline in Myelofibrosis Symptom Assessment Form (MFSAF v4.0) at 12 and 24 weeks

The MFSAF (Myelofibrosis Symptom Assessment Form) should be completed by patients every day for 7 days before Day 1 of each treatment cycle, including the 7 days before starting Cycle 1. It uses a 24-hour recall format, asking patients to rate the worst severity of seven symptoms (fatigue, night sweats, pruritus, abdominal discomfort, pain under the ribs on the left side, early satiety, and bone pain) during the past 24 hours. Each symptom is rated on a scale from 0 (Absent) to 10 (Worst Imaginable). The Total Symptom Score (TSS) is the sum of 7 symptoms (range: 0 - 70). No Change from Baseline indicates stable symptoms (no improvement or worsening), negative change from Baseline indicates a reduction in symptom severity (improvement) and positive change from Baseline indicates an increase in symptom severity (worsening).

Time frame: Baseline, 12 weeks (Cycle 5, Day 1), 24 weeks (Cycle 9, Day 1)

Phase 2 (Arms 1, 2 and 3): Percentage of patients who achieve a ≥ 50% reduction in Total Symptom Score (TSS) at 12 and 24 weeks

The "percentage" of study participants whose TSS-measured by the Myelofibrosis Symptom Assessment Form (MFSAF v4.0)-decreases by at least half compared to their baseline score, when assessed at 12 weeks and again at 24 weeks.

Time frame: 12 weeks (Cycle 5, Day 1), 24 weeks (Cycle 9, Day 1)

Phase 2 (Arms 1, 2 and 3): Overall splenic response rate at 12 and 24 weeks

The overall splenic response rate is the proportion of patients who achieve a ≥ 35% reduction from baseline spleen size by imaging (MRI or CT).

Time frame: 12 and 24 weeks

Phase 2 (Arms 1, 2 and 3): Splenic response at 12 and 24 weeks

The reduction in spleen size from baseline by imaging (MRI or CT) after 12 weeks (Cycle 5, Day 1) and after 24 weeks of treatment (Cycle 9, Day 1) will also be evaluated.

Time frame: 12 and 24 weeks

Phase 2 (Arms 1, 2 and 3): Duration of Transfusion Independence (TI)

Time from first onset of TI to earliest onset of loss of TI.

Time frame: From first onset of TI to earliest onset of loss of TI, assessed up to approximately 6 years

Phase 2 (Arms 1, 2 and 3): Early anemic response rate

Proportion of patients who achieve a hemoglobin increase of ≥1 g/dL from baseline, without RBC transfusions.

Time frame: Through Phase II completion, an average of 6 years

Phase 2 (Arms 1, 2 and 3): Anemic response rate in TI patients

Proportion of TI patients with ≥1.5 g/dL hemoglobin increase from baseline, without RBC transfusions.

Time frame: Through Phase II completion, an average of 6 years

Phase 2 (Arms 1, 2 and 3): Duration of splenic response

Time from first meeting splenic response criteria until loss of response (spleen volume \<35% reduction from baseline and increased by ≥25% from nadir).

Time frame: From first onset of splenic response until loss of response, assessed up to approximately 6 years

Phase 2 (Arms 2 and 4): Maximum observed plasma concentration (Cmax) of pelabresib and ruxolitinib

Pharmacokinetic (PK) parameters will be calculated based on Pelabresib and Ruxolitinib plasma concentrations and actual sampling time points. Cmax will be listed and summarized using descriptive statistics.

Time frame: Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Phase 2 (Arms 2 and 4): Time to reach maximum concentration (tmax) of pelabresib and ruxolitinib

Pharmacokinetic (PK) parameters will be calculated based on Pelabresib and Ruxolitinib plasma concentrations and actual sampling time points. Tmax will be listed and summarized using descriptive statistics.

Time frame: Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Phase 2 (Arms 2 and 4): Predose (trough) concentration at the end of a dosing interval (Ctrough) of pelabresib and ruxolitinib

Pharmacokinetic (PK) parameters will be calculated based on Pelabresib and Ruxolitinib plasma concentrations and actual sampling time points. Ctrough will be listed and summarized using descriptive statistics.

Time frame: Cycle 1 Day 1, Cycle 1 Day 14, Cycle 3 Day 1: predose. 1 cycle = 21 days.

Phase 2 (Arms 2 and 4): Area under the concentration-time curve from time zero to the last observed concentration (AUClast) of pelabresib and ruxolitinib

Pharmacokinetic (PK) parameters will be calculated based on Pelabresib and Ruxolitinib plasma concentrations and actual sampling time points. AUClast will be listed and summarized using descriptive statistics.

Time frame: Cycle 1 Day 14 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose). 1 cycle = 21 days.

Phase 2 (Arms 2 and 4): Area under the concentration-time curve from time zero to 8 hours post-dose at steady state (AUC0-8,ss) of pelabresib and ruxolitinib

Pharmacokinetic (PK) parameters will be calculated based on Pelabresib and Ruxolitinib plasma concentrations and actual sampling time points. AUC0-8,ss will be listed and summarized using descriptive statistics.

Time frame: Cycle 1 Day 14, Cycle 3 Day 1. 1 cycle = 21 days.

Phase 2 (Arms 2 and 4): Maximum concentration at steady state (Cmax,ss) of pelabresib and ruxolitinib

Pharmacokinetic (PK) parameters will be calculated based on Pelabresib and Ruxolitinib plasma concentrations and actual sampling time points. Cmax,ss will be listed and summarized using descriptive statistics.

Time frame: Cycle 1 Day 14, Cycle 3 Day 1. 1 cycle = 21 days.

Phase 2 (Arms 2 and 4): Time to reach maximum concentration at steady state (tmax,ss) of pelabresib and ruxolitinib

Pharmacokinetic (PK) parameters will be calculated based on Pelabresib and Ruxolitinib plasma concentrations and actual sampling time points. Tmax,ss will be listed and summarized using descriptive statistics.

Time frame: Cycle 1 Day 14, Cycle 3 Day 1. 1 cycle = 21 days.

Phase 2 (Arm 4): Percentage of patients who achieve a ≥50% reduction from baseline in the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) total score

The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) is a patient-reported questionnaire designed to measure symptom burden in patients with myeloproliferative neoplasms (MPNs). Patients rate the severity of several symptoms (such as fatigue, night sweats, itching, abdominal discomfort, bone pain, early satiety, and others) over the past 24 hours. Each symptom is scored on a scale from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be). The total score is the sum of all individual symptom scores, providing an overall measure of symptom burden. A 50% reduction in the MPN-SAF total score at 12 or 24 weeks means the patient's overall symptom burden has improved by half compared to their baseline (pre-treatment) score.

Time frame: Baseline, 12 weeks (Cycle 5, Day 1), 24 weeks (Cycle 9, Day 1)

Phase 2 (Arm 4): Partial Hematological Response Rate

Proportion of patients with platelets 400-600 × 10⁹/L, WBC ≤10 × 10⁹/L, confirmed after 1 cycle.

Time frame: Over 2 consecutive cycles (rolling window) (1 cycle = 21 days)

Phase 2 (Arm 4): Overall Hematological Response Rate

Proportion of patients with complete or partial hematological response.

Time frame: Through Phase II completion, an average of 6 years

Phase 2 (Arm 4): Duration of Hematological Response

Time from first onset of response to earliest onset of loss of response, including hematologic response and symptom improvement

Time frame: Through Phase II completion, an average of 6 years

Phase 2 (Arm 4): Rate of hemorrhagic and thromboembolic (TE) events

Proportion of patients with hemorrhagic or TE events.

Time frame: Through Phase II completion, an average of 6 years

A Phase 1/2 Study of CPI-0610 With and Without Ruxolitinib in Patients With Hematologic and Myeloproliferative Malignancies

Overview

Conditions

Interventions

Eligibility

Locations (48)

Outcomes

Primary Outcomes

Secondary Outcomes