CONSTELLATION PHARMACEUTICALS, INC. Item 8.01 Other Events. MANIFEST Trial of CPI-0610
We are currently conducting MANIFEST, a Phase 2 clinical trial of CPI-0610 as a
monotherapy and in combination with ruxolitinib (marketed as Jakafi®/Jakavi®) in
patients with myelofibrosis, or MF, a progressive hematological cancer. We are
enrolling MF patients who are Janus-kinase-1/2, or JAK1/JAK2-, inhibitor-naïve,
a first-line, or 1L, setting, as well as patients who are refractory to or
intolerant of, or have had a sub-optimal response to, ruxolitinib, a
second-line, or 2L, setting. At the Annual Congress of the
In the 1L setting, we are testing CPI-0610 in combination with ruxolitinib in JAK1/JAK2-inhibitor-naïve patients. The primary endpoint in the 1L setting is the proportion of patients who achieve at least a 35% reduction in spleen volume from baseline after 24 weeks of treatment, or SVR35. In the 2L setting, we are stratifying patients for dependence on red-blood-cell, or RBC, transfusions. In transfusion-dependent, or TD, patients, the primary endpoint is the proportion of patients who are transfusion dependent, or TD, at baseline who convert to transfusion independence, or TI. TD, based on Gale criteria, is defined to mean two or more RBC transfusions per month during the 12 weeks prior to enrollment. TI is defined to mean an absence of RBC transfusions over any consecutive 12-week period following enrollment. For non-TD patients in the 2L setting, the primary endpoint is the proportion of patients who achieve SVR35.
In each setting, we are also measuring improvements in Total Symptom Score, or TSS, as measured by the Myelofibrosis Symptom Assessment form, version 4.0, which is a patient-reported outcome that asks patients to rate the severity of their MF symptoms, and Patient Global Impression of Change, or PGIC, which is an assessment of patient's perception of change in their MF symptoms over time. We are also measuring morphological change in bone marrow fibrosis.
Updated Preliminary Data from Our MANIFEST Trial
On
One poster related to Arm 1 of MANIFEST, in which we are evaluating CPI-0610, as a monotherapy in ruxolitinib-refractory or -intolerant patients with MF. A second poster related to Arm 2, in which we are evaluating CPI-0610 in combination with ruxolitinib, in patients with MF with suboptimal response to ruxolitinib. The third poster related to Arm 3 in which we are evaluating the combination of CPI-0610 and ruxolitinib in JAK1/JAK2-inhibitor-naïve patients with MF.
The updated preliminary data showed signs of clinical improvement in spleen volume reduction, patient-reported symptom improvement, hemoglobin increases and conversion to transfusion independence in transfusion-dependent patients. In Arm 1, three of 14 (21.4%) evaluable patients in Cohort 1A, which included patients who were TD at baseline, reported a conversion from TD to TI, and five of 21 (23.8%) evaluable patients in Cohort 1B, which included patients who were not TD at baseline, achieved a SVR35. In Arm 2, 11 of 32 (34.4%) evaluable patients in Cohort 2A, which included patients who were TD at baseline, reported a conversion from TD to TI, and four of 18 (22.2%) evaluable patients in Cohort 2B, which included patients who were not TD at baseline, achieved a SVR35.
In Arm 3, 19 of 30 (63.3%) evaluable patients reported a SVR35, and 17 of 29 (58.6%) evaluable patients reported at least a 50% reduction in TSS, or TSS50, both of which are measures of clinical activity that have been the basis for approval of other existing MF treatments.
As a result of preliminary data in JAK-inhibitor-naïve patients, we are planning to initiate a Phase 3, randomized, double-blind, active-controlled study of CPI-0610 in combination with ruxolitinib in the 1L setting to begin in the second half of 2020.
Arm 1: CPI-0610 Monotherapy in Ruxolitinib-Refractory, -Intolerant or -Ineligible Patients (2L)
In this arm, patients are treated in a 21-day dosing cycle and are administered CPI-0610 starting at 125 mg once per day, which may be titrated up to 225 mg, with 14 days on treatment and seven days off treatment. The primary endpoints are the proportion of patients who achieve a SVR35 for non-TD patients and the rate at which TD patients convert to TI for the cohort of patients who were TD at baseline.
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The tables below present updated preliminary data as ofApril 17, 2020 from Arm 1 of MANIFEST. Arm 1A: TD Arm 1B: non-TD Number of patients enrolled 16 27 SVR35 at 24 weeks1 0 of 10 evaluable 5 of 21 evaluable SVR (%), median change at 24 weeks -17.4% -28.2%
SVR (%), median change range at 24 weeks -38.8% to 64.7% -51.0% to 14.4%
TSS50 at 24 weeks1 1 of 12 evaluable 9 of 19 evaluable TSS (%), median change at 24 weeks -5.8% -55.6%
TSS (%), median change range at 24 weeks -69.9% to 31.7% -100% to 24.7%
Hemoglobin increase of at least 1.5 mg/dL N/A 11 of 19 TD to TI conversion2 3 of 14 evaluable N/A
(1) Patients are evaluable for SVR35 or TSS50 at week 24 if they had a week-24
assessment by the data cutoff date or discontinued treatment after having a
week-12 assessment.
(2) Patients are evaluable for conversion to TI if they had been on treatment for
at least 24 weeks by the data cutoff date or if they had been on treatment
for at least 12 weeks by the data cutoff day and achieved the conversion or
would have failed to achieve the conversion by week 24.
Arm 2: CPI-0610 Add-on to Ruxolitinib in Patients with Suboptimal Response to Ruxolitinib (2L)
In this arm, CPI-0610 is added to treatment with ruxolitinib and CPI-0610 is dosed according to the schedule as in Arm 1 and patients continue treatment with ruxolitinib at their last stable dose with no titration of ruxolitinib. The primary endpoints are the proportion of patients who achieve a SVR35 for non-TD patients and the rate at which TD patients convert to TI for the cohort of patients who were TD at baseline.
The tables below present updated preliminary data as ofApril 17, 2020 from Arm 2 of MANIFEST. Arm 2A: TD Arm 2B: non-TD Number of patients enrolled 44 26 SVR35 at 24 weeks1 5 of 24 evaluable 4 of 18 evaluable SVR (%), median change at 24 weeks -21.9% -15.8% SVR (%), median change range -53.6% to 47.9% -89.8% to 16.3% TSS50 at 24 weeks1 12 of 26 evaluable 7 of 19 evaluable TSS (%), median change at 24 weeks -52.8% -45.0%
TSS (%), median change range at 24 weeks -100% to 24.4% -100% to 21.9% Hemoglobin increase of at least 1.5 mg/dL
N/A 4 of 22
TD to TI conversion2 11 of 32 evaluable2 N/A
(1) Patients are evaluable for SVR35 or TSS50 at week 24 if they had a week-24
assessment by the data cutoff date or discontinued treatment after having a
week-12 assessment.
(2) Patients are evaluable for conversion to TI if they had been on treatment for
at least 24 weeks by the data cutoff date or if they had been on treatment
for at least 12 weeks by the data cutoff day and achieved the conversion or
would have failed to achieve the conversion by week 24.
Arm 3: Combination of CPI-0610 and Ruxolitinib in JAK-Inhibitor-Naïve Patients (1L)
In this arm, patients are treated with CPI-0610 according to the schedule as in Arm 1 and receive either 10 mg or 15 mg twice per day of ruxolitinib, depending on the platelet count at baseline, up to a maximum dose of 20 mg twice per day. The primary endpoint is the proportion of patients who achieve a SVR35.
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The tables below present updated preliminary data as of
Number of patients enrolled 64
SVR35, at 12 weeks1 37 of 51 evaluable
SVR (%), median change at 12 weeks -50.8%
SVR (%), median change range at 12 weeks -90.2% to -2.8%
SVR35 at 24 weeks2 19 of 30 evaluable
SVR (%), median change at 24 weeks -52.9%
SVR (%), median change range at 24 weeks -84.4% to 23.7%
TSS50 at 24 weeks2 17 of 29 evaluable
TSS (%), median change at 24 weeks -64.0%
TSS, median change range at 24 weeks -100% to 24.2%
(1) Patients are evaluable for efficacy at week 12 if they had week 12 spleen
volume assessment by the data cutoff date or discontinued prior to week 12
due to any reason.
(2) Patients are evaluable for efficacy at week 24 if they had a week 24 spleen
volume assessment by the data cutoff date or discontinued due to any reason.
As of
As of
Four patients in Arm 2 and two patients in Arm 3 discontinued treatment due to grade 5 (fatal) adverse events. These adverse events consisted of acute kidney injury, traumatic subdural hematoma (patient tripped and fell), brain stem hemorrhage (patient without concomitant thrombocytopenia), disease progression, multi-organ failure due to sepsis secondary to bacterial endocarditis and heart failure due to sepsis secondary to community acquired pneumonia. The relevant clinical investigator considered the acute kidney injury as possibly related to CPI-0610 and not related to ruxolitinib. The relevant clinical investigator considered the heart failure as possibly related to CPI-0610 and ruxolitinib. The relevant clinical investigators considered the other four grade 5 events as unrelated to CPI-0610.
The most common treatment-emergent adverse events, or TEAEs, of any grade irrespective of causality observed in Arm 1 included nausea, diarrhea, cough, dysgeusia, respiratory tract infections, thrombocytopenia, fatigue, vomiting, pruritus, weight decrease, constipation, abdominal distension, dizziness, pyrexia, headache, peripheral edema, back pain, dyspnea, hyperkalemia, hyperuricemia and pain in extremities, each of which occurred in 10% or more of patients. The most frequently observed grade 3 or higher TEAEs irrespective of causality in Arm 1 were thrombocytopenia (six patients), anemia (four patients), hyperuricemia (three patients), diarrhea, hyponatremia and dyspnea (two patients each). TEAEs of grade 3 or higher considered related to CPI-0610 by clinical investigator consisted of thrombocytopenia (six patients), diarrhea (two patients), acute kidney injury, anemia, blood bilirubin increase, constipation, decreased appetite, dyspnea, hyperglycemia, neutropenia, rash, taste disorder, tumor lysis syndrome and upper abdominal pain (one patient each). Six patients discontinued treatment due to TEAEs.
The most common TEAEs of any grade irrespective of causality observed in Arm 2 included diarrhea, thrombocytopenia, nausea, respiratory tract infections, cough, fatigue, dysgeusia, abdominal pain, decreased appetite, muscle spasms, vomiting, dizziness, arthralgia, pain in extremities, epistaxis, abdominal distension, pyrexia, peripheral edema, back pain, bruising, constipation, dyspnea, anemia, stomatitis, abdominal pain, chills and alanine aminotransferase increase, each of which occurred in 10% or more of patients. The most frequently observed grade 3 or higher TEAEs irrespective of causality in Arm 2 were thrombocytopenia (17 patients), anemia (six patients), fatigue (four patients), neutropenia, diarrhea and respiratory tract infections (three patients each). TEAEs of grade 3 or higher considered related to CPI-0610 by clinical investigator consisted of thrombocytopenia (15 patients), anemia (four patients), neutropenia and diarrhea (three patients each), nausea and fatigue (two patients each), abdominal pain, acute kidney injury, blood creatinine increase, lymphocyte count decrease, vomiting and white blood cell count decrease (one patient each). Seven patients discontinued treatment due to TEAEs.
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The most common TEAEs of any grade irrespective of causality observed in Arm 3 included diarrhea, anemia, thrombocytopenia, nausea, respiratory tract infections, abdominal pain, dysgeusia, fatigue, headache and back pain, each of which occurred in 10% or more of patients. The most frequently observed grade 3 or higher TEAEs irrespective of causality in Arm 3 were anemia (11 patients), thrombocytopenia and respiratory tract infections (three patients each) and dyspnea (two patients). TEAEs of grade 3 or higher considered related to CPI-0610 by clinical investigator consisted of anemia (five patients), thrombocytopenia (three patients), acute myocardial infarction, cardiac failure, duodenal ulcer, hyponatremia, pneumonia, pulmonary sepsis and left ventricular dysfunction (one patient each). Four patients discontinued treatment due to TEAEs.
CPI-1205
We are conducting
Based on additional clinical data from the
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