Clinical trial NCT02215070: Pasireotide in Prevention of GI Toxicity
Official title: Prevention of Gastrointestinal Toxicity From Total Body Irradiation or High Dose Chemotherapy With Pasireotide
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hematological Malignancies
Keywords: Allogeneic Stem Cell Transplantation
Acute Myeloid Leukemia
Acute Lymphoid Leukemia
Acute Non-Lymphocytic Leukemia
Myelodysplastic Syndrome
Chronic Myeloid Leukemia
Lymphoma
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Massachusetts General Hospital
First posted: 2014-08-13
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate if the drug, Pasireotide, is safe and effective in reducing the gastrointestinal side effects of the drugs received to prepare for allogeneic stem cell transplant. The study will also evaluate if Pasireotide is effective in reducing acute and chronic Graft-versus-Host-Disease (GvHD) after transplant.

Detailed description: The study design will be a non-randomized phase II. Forty patients receiving an ablative preparatory regimen will receive pasireotide subcutaneous (0.9 mg, b.i.d.) one day prior to initiation of the preparatory regimen and continuing for eight days following the completion of the preparatory regimen not to exceed 14 days total dosing. We select matched controls from existing patients who did not take the drug to minimize the time it takes to complete the trial.

Myeloablative preparatory regimens are defined as those including either TBI ≥ 1200 cGy or busulfan ≥ 12.8 mg/kg. The most common regimens combine TBI with cyclophosphamide (TBI/Cy) or busulfan with cyclophosphamide (Bu/Cy) (Appendix E). However, any regimen meeting the above definition of myeloablative preparatory regimen may be used.

The study will collect data at screening, at baseline prior to initiation of the drug (day of study drug start), transplant day 0, day +7, day +14 and weekly thereafter until day +100, and on days +180, +270, and +365. The total days on pasireotide therapy will be recorded as well as any SAE that is outside the expected for stem cell transplantation. We will also follow the incidence and severity of acute and chronic GVHD.

At Duke only, a video capsule endoscopy will be performed in a subset of ten study patients between transplant days +4 through +6. This substudy is descriptive in nature and only used to collect a source of preliminary data that may suggest further study.

Patients must agree to participate in this portion of the study and will be asked to sign a clinical consent for performance use of the video capsule endoscopy. Patients will be given detailed instructions to prepare for the procedure. An investigator who is blinded to the group allocation of the patients/volunteers separately will review the images obtained from each of the capsule examinations. Images will be examined for evidence of the four following types of abnormalities: reddened/edema/villous blunting, erosion, ulcer and stenosis. Each of these categories will be scored from 0-3 and summed to obtain an overall index that will range from 0 (normal study) to 12 (severely abnormal in all categories).

Citrulline assay Measurement of citrulline concentration has been used as a marker for cytotoxic treatment-induced intestinal damage and it is highly reproducible. The citrulline concentration appears to be a quantitative parameter that is independent of the underlying cause for epithelial cell loss and functions well in the post-SCT setting. Six mls of blood will be collected in heparinized tubes on days 0, 7, and 14. Tubes will be centrifuged according to manufacturer's instructions and the plasma will be collected and stored at -80C until shipment to the laboratory performing the assay.

Calprotectin assay Calprotectin has been described as another biomarker of GI injury. During radiation-induced inflammation, leucocytes infiltrate the mucosa and increase the level of fecal calprotectin. At least 50 mg of stool specimen will be collected from patients on days 0, 7, and 14. Samples will be stored at -80C until shipment to the laboratory performing the assay. Calprotectin will be measured with an ELISA kit (CALPRO, Oslo, Norway) in accordance with the manufacturer's instructions.

Eligibility criteria: Inclusion Criteria:

* 18 years of age or older at the time of study enrollment.
* Histologically confirmed diagnosis for which an allogeneic transplant is utilized.
* Plan to receive an allogeneic transplant from a 4-6/6 single or dual umbilical cord blood graft, or a 7-8/8 HLA-matched sibling or unrelated donor (High resolution HLA-A, B, C, DRB1).
* Meet standard criteria as defined by the institution for a myeloablative allogeneic stem cell transplantation, with myeloablative defined as using conditioning regimens containing:

  * TBI ≥ 1200 cGy, or
  * Busulfan ≥ 12.8mg/kg
* Patient must have given written informed consent according to FDA guidelines.
* Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures.

Exclusion Criteria:

* Female patients who are pregnant or lactating, or are of childbearing potential (FCBP, defined as all women physiologically capable of becoming pregnant) and not practicing an effective method of contraception/birth control
* FCBP must have a current negative serum pregnancy test prior to transplant per institutional practice.
* Use of an investigational drug within 1 month prior to dosing. Concurrent enrollment on other clinical research studies that contain an interventional therapy is not permitted while subjects are receiving pasireotide or within 5 half-lives of finishing pasireotide. However, subjects may concurrently enroll in non-interventional studies (e.g. biobanking, mobile health tracking).
* Active CNS disease (related to primary malignancy) at the time of enrollment.
* Patients with existing grade 2 toxicities, except as approved by the investigator.
* Any of the following diseases or conditions:

Cardiac:

* History of unexplained syncope or family history of idiopathic sudden death.
* Sustained or clinically significant cardiac arrhythmias.
* Risk factors for Torsades de Pointes such as:

  * Uncontrolled hypokalemia
  * Uncontrolled hypomagnesemia or hypermagnesemia
  * Cardiac failure (New York Heart Association Class II or higher)
  * Clinically significant/symptomatic bradycardia (HR \< 50), or high-grade AV block.
  * Known diagnosis of QT prolongation (QTc ≥ 470) or family history of long QT syndrome
  * Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by diabetes, or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism or cardiac failure.
  * Concomitant medications known to prolong the QT interval during the same time as pasireotide is to be administered (unless approved by PI and QTc \< 470; standard transplant medications that are known to prolong the QT (e.g. azoles, ondansetron, etc.) are permitted but caution is advised and patients should be closely monitored).

Endocrine:

* Uncontrolled diabetes at the time of cytoreduction. All patients with diabetes must be optimized on their diabetes regimen prior to initiating pasireotide.

  • If a patient is diabetic: uncontrolled diabetes as defined by HbA1c \> 8 per cent despite adequate therapy
* Patients who are not biochemically euthyroid. Patients with known history of hypothyroidism are eligible if they are on adequate and stable replacement thyroid hormone therapy for at least 3 months.
* Known diagnosis of hypocortisolism
* Known diagnosis of pituitary hormone deficiency.
* Known hypersensitivity to somatostatin analogs or any component of the pasireotide LAR or s.c. formulations.

Infectious:

* Uncontrolled (not being treated) infections at the time of cytoreduction.
* A positive HIV test result (ELISA and Western blot) or history of known HIV. An HIV test will not be required; however, previous medical history will be reviewed.

Gastrointestinal:

* Moderately impaired hepatic function (Child-Pugh B) or severe hepatic impairment (Child-Pugh C)
* Known gallbladder or bile duct disease, symptomatic cholelithiasis, acute or chronic pancreatitis.
* Known malabsorption syndrome, short bowel or chologenic diarrhea not controlled by specific therapeutic means.

Hematologic:

* Abnormal coagulation (PT or aPTT \> 30% above normal limits).
* Continuous anticoagulation therapy. Patients who were on anticoagulant therapy must complete a washout period of at least 10 days and have confirmed normal coagulation parameters before study inclusion.

Miscellaneous:

* Major surgery/surgical therapy for any cause within 1 month prior to pasireotide administration. Patients should have recovered and have a good clinical condition before entering the study.
* Any co-morbid condition which, in the view of the Principal Investigator, renders the patient at high risk from treatment complications.

Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study.

Primary outcomes:
measure: Percentage of GI Toxicity From the Preparatory Regimen and the GVHD Prophylaxis in Stem Cell Transplantation (SCT) Patients Who Are Treated With Pasireotide
timeFrame: 30 Days
Secondary outcomes:
measure: Percentage of Acute GVHD
timeFrame: 100 days
measure: Maximum Severity of Acute GVHD Compared to Historical Controls
timeFrame: 100 days
measure: Incidence of Chronic GVHD Compared to Historical Controls
timeFrame: 1 year
measure: Maximum Severity of Chronic GVHD Compared to Historical Controls
timeFrame: 1 year
measure: Overall Survival Compared to Historical Controls
timeFrame: 1 year
measure: Disease Free Survival Compared to Historical Controls
timeFrame: 1 year
Other outcomes:
measure: Citrulline and Fecal Calprotectin Levels Will be Measured
timeFrame: 100 days
measure: Evaluate GI Toxicity Assessment by Video Capsule Endoscopy.
timeFrame: 14 days
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
Study officials:
affiliation: Duke University
name: Anthony Sung, MD
role: PRINCIPAL_INVESTIGATOR
References: