Safety and Tolerability of PF-05230907 in Intracerebral Hemorrhage

A PHASE 1B MULTICENTER, OPEN-LABEL STUDY TO EVALUATE THE SAFETY AND TOLERABILITY AND DETERMINE THE MAXIMUM TOLERATED DOSE OF PF-05230907 IN SUBJECTS WITH INTRACEREBRAL HEMORRHAGE (ICH)

B2341002 was terminated on 26-OCT-2017 for strategic reasons. The decision to terminate the trial was not based on any safety concerns.

This study employs a modified continual reassessment method (mCRM) design to estimate the maximum tolerated dose (MTD) of PF-05230907, defined as a target toxicity rate of 15% based on treatment emergent thromboembolic and/or ischemic events (TIEs). The mCRM design utilizes Bayesian methodology to continuously learn the dose-toxicity relationship, which is characterized by a parametric model. Subjects with a diagnosis of ICH (determined by computed tomography) will be enrolled in cohorts of 3. The total length of time planned for study participation is approximately 3 months; 6.0 hours for screening, a single dose administration with a 4-day minimum hospital confinement period and follow-up visits through Day 91. Severity of adverse events (AEs) and serious adverse events (SAEs) will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. All subjects who receive PF-05230907 are evaluable for TIEs. The determination of MTD using mCRM modeling will be based on TIEs which occur through 7 days post-dose (Day 8).

safety, maximum tolerated dose, modified continual reassessment method, intracerebral, hemorrhage, hematoma

Thromboembolic and/or ischemic events (TIEs) were defined as any of the following events: disseminated intravascular coagulation (Grade [Gr]>=3); acute coronary syndrome (Gr >=3); cardiac arrest (Gr >=4); myocardial infarction (Gr >=3); Cardiac troponin I increased (Gr 3); ischemia cerebrovascular (Gr >=1 and associated with lesion[s]); portal vein thrombosis (Gr >=2); ischemic stroke (Gr >=1 and associated with lesion[s]); transient ischemic attacks (Gr 2); purpura (Gr >=2); superior vena cava syndrome (Gr >=1); thromboembolic event (Gr >=2); visceral arterial ischemia (Gr >=2); peripheral arterial ischemia (Gr >=3). TIEs were graded based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For the respective event to count as a treatment-emergent TIE, onset or worsening of the event must have occurred following treatment with PF-05230907 and during the interval between Day 1 dosing through Day 8.

A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death; or was life threatening (immediate risk of death); or required inpatient hospitalization or prolongation of existing hospitalization; or resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); or resulted in congenital anomaly/birth defect. Any such events occurring following the start of treatment or increasing in severity were counted as treatment-emergent.

An adverse event (AE) was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. For the respective event to count as a treatment-emergent AE, onset or worsening of the event must have occurred following treatment with PF-05230907 and during the interval between Day 1 dosing through Day 8.

Laboratory safety parameters included hematology, blood chemistry, prothrombin time/international normalized ratio (PT/INR), fibrinogen, antithrombin III (ATIII), Protein S level, Protein C activity, cardiac troponin I, D-dimer, and urinalysis. The number of participants with laboratory test abnormalities meeting specified criteria without regard to baseline abnormality was assessed. Any abnormalities occurring after the administration of treatment and increasing in severity from baseline value were counted as treatment-emergent.

Day 1 through Day 8 (or discharge) for D-dimer laboratory test and urinalysis; Day 1 through Day 4 for all other laboratory tests

Comprehensive and targeted physical examinations included general appearance, HEENT (head, eyes, ears, nose and throat), skin, heart (auscultation), lungs (auscultation), abdomen (palpitation and auscultation), and extremities with attention to swelling, general or localized tenderness, entire leg or calf swelling, edema, and collateral superficial veins. The results of the comprehensive and targeted physical examinations were combined to evaluate the changes from baseline through Day 8 (or discharge) for each site parameter according to the categories: positive change (abnormal to normal); no change (normal to normal or abnormal to abnormal); negative change (normal to abnormal). Parameters with at least 1 participant meeting the positive/negative change from baseline criteria are presented here.

Respiratory rate was measured after 5 minutes rest in supine position by observing and counting the respirations of the participant for 30 seconds and multiplied by 2. The use of an automated device for measuring respiratory rate was acceptable.

Supine blood pressure (BP, systolic and diastolic) was measured with the participant's arm supported at the level of the heart and recorded to the nearest milliliters of mercury (mmHg) after 5 minutes of rest whenever possible and as permitted by the participant's medical condition.

The use of an automated device for measuring pulse rate was acceptable, although, when done manually, pulse rate was measured in the brachial/radial artery for at least 30 seconds.

The electrocardiogram (ECG) results over time were compared to baseline and assessed by the investigator as "less abnormal", "no significant change", or "more abnormal".

Maximum changes from baseline were calculated for activated partial thromboplastin time (aPTT) after dosing with PF-05230907 through Day 2.

Maximum changes from baseline were calculated for prothrombin fragment 1+2 (PF1+2) after dosing with PF-05230907 through Day 2.

Participants with anti-drug antibody (ADA) production were those with at least 1 positive result from Day 1 through follow-up visit (Day 43 and/or Day 91). ADA positive: titer value >=1.88.

ADA positive samples were planned to be further characterized for neutralizing antibody (NAb). Participants with NAb production were those with at least 1 positive result from Day 1 through follow-up visit (Day 43 and/or Day 91). As all ADA samples were negative (titer value <1.88), NAb analysis was not conducted.

Participants with anti-Chinese hamster ovary (CHO) antibody production were those with positive results. Positive: titer value >=2.00.

Number of Participants With Anti-Paired Basic Amino Acid Cleaving Enzyme (PACE) Furin Antibody Production

Participants with anti-paired basic amino acid cleaving enzyme (PACE) antibody production were those with positive results. Positive: titer value >=2.00.

The National Institute of Health Stroke Scale (NIHSS) is a 15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. The total NIHSS score range is from 0 (normal) to 42 (severe impairment), with higher values indicating greater level of neurological impairment.

Maximum duration for 4 types of hospital or health care unit: Intensive Care Unit (ICU), general ward, rehabilitation center, and other hospital units. This was an exploratory endpoint to evaluate information for designing future studies, which were no longer planned.

Inclusion Criteria: ICH as documented by CT scan within 6.0 hours of symptom onset Baseline ICH volume > 5mL and < 60 mL Exclusion Criteria: Deep coma (Glasgow Coma Scale < 6) Modified Rankin Score > 3 prior to ICH onset Known history of schemic, vaso-occlusive or thrombotic events within 6 months prior to screening Known prothrombotic disorders Known secondary ICH related to aneurysm, arteriovenous malformation, subarachnoid hemorrhage, trauma, or other causes. CT angiography, MR, or other diagnostic studies obtained as part of the standard of care may be used to assess eligibility. Known use of oral anticoagulant(s) Known use of low-molecular weight heparin or heparin

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Silva Blas Y, Diringer MN, Lo B, Masjuan J, Perez de la Ossa N, Cardinal M, Yong F, Zhu T, Li G, Arkin S. Phase 1b Study to Evaluate Safety, Tolerability, and Maximum Tolerated Dose of PF-05230907 for Intracerebral Hemorrhage. Stroke. 2021 Jan;52(1):294-298. doi: 10.1161/STROKEAHA.120.029789. Epub 2020 Dec 4.

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