Clinical trial NCT03362502: A Study to Evaluate the Safety and Tolerability of PF-06939926 Gene Therapy in Duchenne Muscular Dystrophy
Official title: A PHASE 1B MULTICENTER, OPEN-LABEL, SINGLE ASCENDING DOSE STUDY TO EVALUATE THE SAFETY AND TOLERABILITY OF PF-06939926 IN AMBULATORY AND NON-AMBULATORY SUBJECTS WITH DUCHENNE MUSCULAR DYSTROPHY
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Duchenne Muscular Dystrophy
Keywords: gene therapy
mini-dystrophin
AAV
fordadistrogene movaparvovec
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2017-12-05
Enrollment: 23
Sex: MALE
Minimum age (years): 4
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is a first-in-human/first-in-patient, multi-center, open-label, non-randomized, ascending dose, safety and tolerability study of a single intravenous infusion of PF-06939926 in ambulatory and non-ambulatory subjects with Duchenne muscular dystrophy (DMD). Other objectives include measurement of dystrophin expression and distribution, and assessments of muscle strength, quality, and function.

A total of approximately 22 subjects will receive PF-06939926, and these will include both ambulatory and non-ambulatory subjects. Up to 13 subjects may be included in a cohort that includes the concomitant medication, sirolimus. In order to mitigate unanticipated risks to subject safety, enrollment will be staggered within and between two planned dose-levels and will include a formal review by an external data monitoring committee (E-DMC) prior to dose progression.


Eligibility criteria: Inclusion Criteria:

* Age as follows, based on ambulatory status:

  * FOR AMBULATORY PARTICIPANTS, defined as the ability to walk at least 10 meters unassisted: Between 4 and 12 years, inclusive,
  * FOR NON-AMBULATORY PARTICIPANTS, defined as the inability to walk at least 10 meters unassisted: No age restrictions so long as loss of ambulation occurs prior to the subject's 17th birthday;
* Diagnosis of Duchenne muscular dystrophy confirmed by medical history and genetic testing;
* Receipt of glucocorticoids for 6 months and a stable daily dose for at least 3 months prior to study entry;
* Ability to tolerate magnetic resonance imaging (MRI) without sedation and with no contraindications to these procedures;
* Ability to tolerate muscle biopsies under anesthesia with no contraindications to these procedures;
* Body weights as follows, based on ambulatory status:

  * FOR AMBULATORY PARTICIPANTS: Between 15 kg and 50 kg,
  * FOR NON-AMBULATORY PARTICIPANTS: Less than 75 kg, but which may be managed or adjusted to a lower limit, especially to ensure participant safety;
* Functional performance as follows, based on ambulatory status:

  * FOR AMBULATORY PARTICIPANTS: Ability to rise from floor within seven (7) seconds,
  * FOR NON-AMBULATORY PARTICIPANTS: Percent predicted forced vital capacity greater than 40% as part of pulmonary function tests, as well as adequate upper limb function.

Exclusion Criteria:

* Receipt of live attenuated vaccination within 3 months prior to receiving PF-06939926 or exposure to an influenza (or other inactivated) vaccination or systemic antiviral and/or interferon therapy within 30 days prior to receipt of PF-06939926;
* Prior exposure to any gene therapy agent, including exon-skipping agents;
* Exposure to other investigational drugs within 30 days or 5 half-lives, whichever is longer;
* Neutralizing antibodies (NAb) against adeno-associated virus, serotype 9 (AAV9);
* Compromised cardiac function as indicated by left ventricular ejection fraction on cardiac MRI, as follows, based on ambulatory status:

  * FOR AMBULATORY PARTICIPANTS: Less than 55%,
  * FOR NON-AMBULATORY PARTICIPANTS: Less than 35%;
* Inadequate hepatic or renal function or risk factors for autoimmune disease on screening laboratory assessments.
* The following genetic abnormalities in the dystrophin gene as confirmed by the investigator based on the review of the DMD genetic testing:

  1. Any mutation (exon deletion, exon duplication, insertion, or point mutation) affecting any exon between exon 9 and exon 13, inclusive; OR
  2. A deletion that affects both exon 29 and exon 30.

Sirolimus Cohort

Inclusion Criteria

* \> 8 years of age Exclusion Criteria
* Hypersensitivity to sirolimus or intolerance to soy, including a history of angioedema
* Concomitant use with strong CYP3A4/P-gp inducers or inhibitors

Primary outcomes:
measure: Number of Participants With All-Causality Treatment-Emergent Adverse Events (TEAEs) for 1-Year Follow-Up
timeFrame: Baseline up to 1 year post dose of PF-06939926
measure: Number of Participants With All-Causality TEAEs by System Organ Class (SOC) and Preferred Term (PT) for 1-Year Follow-Up
timeFrame: Baseline up to 1 year post dose of PF-06939926
measure: Number of Participants With Treatment-Related TEAEs for 1-Year Follow-Up
timeFrame: Baseline up to 1 year post dose of PF-06939926
measure: Number of Participants With Treatment-Related TEAEs by SOC and PT for 1-Year Follow-Up
timeFrame: Baseline up to 1 year post dose of PF-06939926
measure: Number of Participants With All-Causality SAEs by SOC and PT for 1-Year Follow-Up
timeFrame: Baseline up to 1 year post dose of PF-06939926
measure: Number of Participants With Treatment-Related SAEs by SOC and PT for 1-Year Follow-Up
timeFrame: Baseline up to 1 year post dose of PF-06939926
measure: Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality for 1-Year Follow-Up - Hematology
timeFrame: Baseline up to 1 year post dose of PF-06939926
measure: Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality for 1-Year Follow-Up - Clinical Chemistry
timeFrame: Baseline up to 1 year post dose of PF-06939926
measure: Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality for 1-Year Follow-Up - Urinalysis
timeFrame: Baseline up to 1 year post dose of PF-06939926
measure: Change From Baseline on Left Ventricular Ejection Fraction as Measured by Cardiac Magnetic Resonance Imaging (MRI) for 1-Year Follow-Up
timeFrame: Baseline, 1 year post dose of PF-06839926 (Day 360)
measure: Number of Participants With Electrocardiograms (ECGs) Meeting the Pre-Defined Categorical Criteria for 1-Year Follow-Up
timeFrame: Baseline up to 1 year post dose of PF-06939926
measure: Number of Participants With Positive Responses on Columbia-Suicide Severity Rating Scale (C-SSRS) According to the Columbia Classification Algorithm of Suicide Assessment (C-CASA) Categories
timeFrame: Baseline, Day 7, Day 14, Day 180, and Day 360
measure: Number of Participants With Vital Signs Meeting the Pre-Defined Categorical Criteria for 1-Year Follow-Up
timeFrame: Baseline up to 1 year post dose of PF-06939926
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: MRI Research Center
state: California
city: Los Angeles
country: United States
facility: Reed Neurological Research Center
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center (Investigational Drug Section)
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center - Interventional Radiology
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center Drug Information Center
state: California
city: Los Angeles
country: United States
facility: UCLA (David Geffen School of Medicine)
state: California
city: Los Angeles
country: United States
facility: UCLA Children's Heart Center
state: California
city: Los Angeles
country: United States
facility: UCLA Mattel Children's Hospital
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA Outpatient Surgery Center
state: California
city: Durham
country: United States
facility: Duke Neurology
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center, Lenox Baker Children's Hospital
state: North Carolina
city: Durham
country: United States
facility: Biospecimen Repository & Processing Core - BPRC
state: North Carolina
city: Durham
country: United States
facility: Duke Cardiovascular Magnetic Resonance Center
state: North Carolina
city: Durham
country: United States
facility: Duke Children's Hospital & Health Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Hospital Investigational Drug Services (IDS) Pharmacy
state: North Carolina
city: Salt Lake City
country: United States
facility: CCTS Clinical Research Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah Imaging and Neurosciences Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah Hospital & Clinics Investigational Drug Services
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah Hospital
state: Utah
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah Clinical Neurosciences Center
state: Utah
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: