Clinical trial NCT04401267: Hypertension Intervention to Reduce Osteonecrosis in Children With Acute Lymphoblastic Leukemia/Lymphoma
Official title: Hypertension Intervention to Reduce Osteonecrosis in Children With Acute Lymphoblastic Leukemia/Lymphoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Hypertension
Osteonecrosis
Osteonecrosis Due to Drug
Keywords: Acute Lymphoblastic Leukemia
Children
Hypertension
Osteonecrosis
Osteonecrosis Due to Drug
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2020-05-26
Enrollment: 51
Sex: ALL
Minimum age (years): 10
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomized unblinded Phase II clinical trial evaluating the impact of intensive antihypertensive control (targeted to the 50-75th percentile for age, sex, and height) compared to conventional antihypertensive control (targeted to the 90-95th percentile for age, sex, and height) on the incidence of radiographically extensive osteonecrosis in children and young adults receiving treatment for newly diagnosed acute lymphoblastic leukemia/lymphoma (ALL).

Primary Objective

* Compare the frequency of radiographically extensive osteonecrosis in patients receiving intensive compared to conventional antihypertensive therapy.

Secondary Objectives

* Evaluate the efficacy of intensive antihypertensive control compared to conventional antihypertensive control in the prevention of clinically significant (CTCAE Grade 2 or higher) and radiologically extensive osteonecrosis, overall and stratified by joints.
* Compare the frequency of clinically significant and radiographically extensive osteonecrosis in patients receiving antihypertensive therapy and historical controls.
* Compare blood pressures achieved in intensive and conventional arms using both pressures obtained as part of routine patient care and ambulatory blood pressure monitoring.
* Compare levels of vascular dysfunction as measured physiologically, radiographically, and in blood samples in patients receiving intensive compared to standard antihypertensive therapy.

Exploratory Objectives

* Identify predictive patterns of blood biomarkers which identify patients at high- risk of developing clinically significant osteonecrosis.
* Identify MRI findings during late induction which correlate with osteonecrosis lesions seen during reinduction.
* Identify patterns of diurnal blood pressure variation as measured by ambulatory blood pressure monitoring associated with the later development of osteonecrosis.
* Compare induction blood pressure control and intervention arm to echocardiographic changes at reinduction II.
* Evaluate patient-reported, health-related quality of life in patients during induction and after 1.5 years of therapy when many experience the symptoms of osteonecrosis.

Detailed description: Patient randomization will be stratified based on patient's location (Memphis vs. other), use of antihypertensives prior to randomization, and factors known to influence osteonecrosis risk, specifically sex and self-declared race (non-Hispanic white vs. other). A target systolic blood pressure range will be chosen for each participant based on their randomization arm, age, sex, and height.

Patients will be randomized on day 4 of induction therapy to either conventional or intensive blood pressure goals. Patients will be treated with antihypertensive therapy to achieve blood pressure control as indicated by their randomized arm. Therapy will be adjusted every 3-4 days as needed to achieve targeted control based on the mean of blood pressures obtained in that period. Treatment of hypertension to the target will continue until the completion of reinduction II therapy. Patients will be evaluated for osteonecrosis as indicated in their primary therapeutic protocol using MRI during reinduction II.

Patients will be asked to complete a symptom survey and a semi-structured interview.

Eligibility criteria: Inclusion Criteria:

* Patient is being treated for newly diagnosed acute lymphoblastic leukemia or lymphoma (ALL) on the TOT17 protocol. Patients do not need to be hypertensive to enroll.
* Patient is 10 years of age or older at the time of enrollment on TOT17.
* Patient has completed ≤ 4 days of protocol therapy (patients are eligible on Day 4 of TOT17 therapy).

Exclusion Criteria:

* Moderate-severe renal dysfunction (glomerular filtration rate \<45 ml/min/1.73m2).
* Down's syndrome (germline Trisomy 21) or other syndrome resulting in growth delay or alterations in stature.
* Chronic inability to ambulate. Patients with limitations in movement due to acute complications of leukemia/lymphoma are not excluded.
* Permanent contraindication to MRI evaluation.
* Participants who are pregnant or lactating. Males or females of reproductive potential must agree to use effective contraception for the duration of study participation.
* Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

Primary outcomes:
measure: Extensive Radiographic Osteonecrosis
timeFrame: during reinduction II therapy, approximately 9 months into therapy.
Secondary outcomes:
measure: Rate of Clinically Significant Osteonecrosis
timeFrame: any time during leukemia therapy, approximately 2.5 years
measure: Rate of Clinically Significant Osteonecrosis vs. Historical Control
timeFrame: any time during leukemia therapy, approximately 2.5 years
measure: Blood Pressure Control on Trial
timeFrame: first 9 months of therapy
measure: Biomarkers of Vascular Dysfunction - eNO Synthetase (pg/mL)
timeFrame: 3 weeks and 9 months into therapy
measure: Biomarker of Vascular Dysfunction - Von Willebrand Factor (%)
timeFrame: 3 weeks and 9 months into therapy
measure: Biomarker of Vascular Dysfunction - TNF-alpha (pg/mL)
timeFrame: 3 weeks and 9 months into therapy
measure: Biomarker of Vascular Dysfunction - D-dimer (µg/mL)
timeFrame: 3 weeks and 9 months into therapy
measure: Biomarker of Vascular Dysfunction - PAI-1 (AU/mL)
timeFrame: 3 weeks and 9 months into therapy
measure: Biomarker of Vascular Dysfunction - E-selectin (ng/mL)
timeFrame: 3 weeks and 9 months into therapy
measure: Biomarker of Vascular Dysfunction - ICAM-1 (ng/mL)
timeFrame: 3 weeks and 9 months into therapy
measure: Biomarker of Vascular Dysfunction - Arterial Elasticity (ml/mmHg)
timeFrame: 3 weeks and 3 months into therapy
measure: Biomarker of Vascular Dysfunction - Pulse Wave Velocity (m/Sec)
timeFrame: 3 weeks and 3 months into therapy
measure: Magnetic Resonance Imaging (MRI) of Right and Left Hip and Knee
timeFrame: 3 weeks and 9 months into therapy
Other outcomes:
Locations:
city: Charlotte
country: United States
facility: St. Jude Affiliate Clinic - Novant Health Hemby Children's Hospital
state: North Carolina
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Seth E. Karol, MD
role: PRINCIPAL_INVESTIGATOR
References: