Stem Cell Monitoring for CML Patients Undergoing Nilotinib Therapy

• Sponsor: Weill Medical College of Cornell University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02353728
• Collaborator: Novartis Pharmaceuticals (Industry)
• Enrollment: 16
• Location: 1
• Arm: 1
• Actual Duration (Months): 73
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The study is an open-label phase 2 clinical and translational trial designed to evaluate the effects of nilotinib on the leukemic stem cell population in subjects with newly diagnosed chronic phase chronic myeloid leukemia (Ph+ CML in CP). Nilotinib is FDA-approved to treat subjects with Ph+ CML in CP. Subjects on study will be monitored according to accepted National Cancer Comprehensive Network [NCCN] clinical guidelines for 24 months. After 24 months, if continued therapy is needed subjects will be transitioned to commercial supply of study drug.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myeloid Leukemia	Drug: Nilotinib	Phase 2

Detailed Description

Patients with newly diagnosed Ph+ CML in chronic phase will be eligible for enrollment in this trial. Prior treatment with nilotinib for less than 2 weeks and hydroxyurea is allowed.

Before therapy and during therapy, peripheral blood and bone marrow samples will be obtained for cytogenetic and molecular evaluations. During study, blood will be collected at approximately month 1, month 3, and every 3 months thereafter; aspirate samples will be collected at approximately month 1, month 3, and month 12. These samples will be collected to analyze the quantitative and qualitative changes in the leukemic stem cell population before and during therapy with nilotinib. The study is intended as a hypothesis finding analysis in order to establish whether in response to nilotinib therapy, defined differences in the baseline or therapy-induced changes in the characteristics of the stem cell population will be predictive of the ability to successfully discontinue therapy in subjects with CML.

In order to determine the effect of nilotinib in stem and progenitor populations we will evaluate 40 newly diagnosed CML subjects undergoing treatment with nilotinib at different time points. We will evaluate the levels of expression of Breakpoint Cluster Region-Abelson protooncogene (BCR-ABL) in purified stem cell populations during the course of treatment. In addition, we will compare the stem and progenitor populations present during the course of treatment in peripheral blood and bone marrow. We will perform transcriptional profiling of such populations to determine changes in signaling pathways driving survival, self-renewal or proliferation. Whole exome sequencing will be also performed in all diagnostic samples to determine whether there are novel cooperating mutations.

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Detection, Monitoring, and Molecular Characterization of Leukemic Stem Cells From Patients With Chronic Myeloid Leukemia (CML) Undergoing Therapy With Nilotinib
• Actual Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Feb 1, 2021
• Actual Study Completion Date: Feb 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: All Patients Nilotinib at a dose of 300 mg P.O. twice a day (BID) daily	Drug: Nilotinib; Other Names: Tasigna AMN107

Outcome Measures

Primary Outcome Measures

1. Percentage of Leukemic Stem Cells Present in Bone Marrow Aspirate Samples, in This Patient Population [1 month, 3 months, 12 months]

   The data obtained from these bone marrow samples, from these patients, may identify stem cell variables that can more accurately predict the success of discontinuation of tyrosine kinase inhibitor (TKI) therapy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients 18 years or older

2. Eastern Cooperative Oncology Group (ECOG) Performance status 0,1, or 2

3. Documented diagnosis of Ph+ Chronic phase CML:

• Chronic phase: None of the criteria for accelerated or blastic phase

• Accelerated phase

1. Blasts ≥ 15% in blood or BM

2. Blasts plus progranulocytes ≥ 30% in blood or bone marrow (BM)

3. Basophilia ≥ 20% in blood or BM

4. Platelets < 100 × 109/L unrelated to therapy

5. Cytogenetic clonal evolution

• Blast phase

1. ≥ 30% blasts in blood or BM

2. Extramedullary disease with localized immature blasts

3. Adequate end organ function, defined as the following:

• Creatinine < 1.5 x upper limit of normal (ULN)

• Absolute neutrophil count (ANC) > 1.5 x 109/L

• Platelets > 100 x 109/L

• Total bilirubin < 1.5 x ULN (Does not apply to patients with isolated hyperbilirubinemia [e.g., Gilbert's disease] grade <3)

• Aspartate aminotransferase (AST) (SGOT) and Alanine aminostransferase (ALT) (SGPT) < 3 x ULN

• Serum amylase and lipase ≤ 2 x ULN

• Alkaline phosphatase ≤ 2.5 x ULN

• Patients must have the following laboratory values (WNL = within normal limits at the local institution lab) or corrected to within normal limits with supplements prior to the first dose of study medication:

1. Potassium (WNL)

2. Magnesium (WNL)

3. Phosphorus (WNL)

4. Calcium (WNL)

Exclusion Criteria:

1. Previous treatment with any other tyrosine kinase inhibitor except for up to 2 weeks of nilotinib

2. Impaired cardiac function including any one of the following:

• Inability to monitor the QT interval on ECG

• Congenital long QT syndrome or a known family history of long QT syndrome.

• Clinically significant resting brachycardia (<50 beats per minute)

• Q-T Corrected (corrected Q-T interval) (QTc) > 450 msec on baseline ECG. If QTc

450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc

• Myocardial infarction within 12 months prior to starting study Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension)

• History of or presence of clinically significant ventricular or atrial tachyarrhythmias

• Complete left bundle branch block

• Right bundle branch block plus left anterior/posterior hemiblock

• Use of ventricular-paced pacemaker

• History of unstable angina within 1 year of study entry

1. Patients currently receiving treatment with strong CYP3A4 inhibitors and treatment cannot be either discontinued or switched to a different medication prior to starting study drug. (http://medicine.iupui.edu/clinpharm/ddis/) ).

2. Patients currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug (http://crediblemeds.org/)

3. Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery).

4. History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis

5. Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, uncontrolled infection)

6. History of another active malignancy within 5 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively

7. Known presence of significant congenital or acquired bleeding disorder unrelated to cancer

8. Major surgery within 4 weeks prior to Day 1 of the study or who have not recovered from prior surgery

9. Treatment with other investigational agents within 30 days of Day 1.

10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of female after conception and until the termination of gestation, confirmed by a positive Human chorionic gonadotropin (hCG) laboratory test. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during the study and for 14 days after the final dose of nilotinib.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Weill Cornell Medical College	New York	New York	United States	10065

Sponsors and Collaborators

• Weill Medical College of Cornell University
• Novartis Pharmaceuticals

Investigators

• Principal Investigator: Ellen K Ritchie, MD, Associate Professor of Clinical Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 10, 2016

More Information

Publications

None provided.

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT02353728
• Other Study ID Numbers: 1403014950
• First Posted: Feb 3, 2015
• Last Update Posted: Mar 25, 2022
• Last Verified: Mar 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Study Results

Participant Flow

Arm/Group Title	All Patients
Arm/Group Description	Nilotinib at a dose of 300 mg P.O. twice a day (BID) daily Nilotinib
Period Title: Overall Study
STARTED	16
COMPLETED	15
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	All Patients
Arm/Group Description	Nilotinib at a dose of 300 mg P.O. twice a day (BID) daily Nilotinib
Overall Participants	16
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	2 12.5%
>=65 years	14 87.5%
Sex: Female, Male (Count of Participants)
Female	8 50%
Male	8 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 6.3%
White	5 31.3%
More than one race	0 0%
Unknown or Not Reported	10 62.5%
Region of Enrollment (participants) [Number]
United States	16 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Leukemic Stem Cells Present in Bone Marrow Aspirate Samples, in This Patient Population
Description	The data obtained from these bone marrow samples, from these patients, may identify stem cell variables that can more accurately predict the success of discontinuation of tyrosine kinase inhibitor (TKI) therapy.
Time Frame	1 month, 3 months, 12 months

Outcome Measure Data

Analysis Population Description

16 patients were treated, 7 patients were not evaluable due to bone marrow samples not being available. Not all timepoints for each patient are reported due to bone marrow samples not being available. Bone marrow samples were not available due to: samples not being collected from a bone marrow procedure; bone marrow procedures not being performed so no sample could be obtained; or collected or sample was not evaluable.

Arm/Group Title	All Patients
Arm/Group Description	Nilotinib at a dose of 300 mg P.O. twice a day (BID) daily Nilotinib
Measure Participants	9
WCMC-007 (3 months)	37.4
WCMC-010 (1 month)	2.32
WCMC-011 (12 months)	0.7
WCMC-013 (1 month)	7.04
WCMC-013 (12 months)	24.2
WCMC-014 (1 month)	9.57
WCMC-014 (3 month)	14.6
WCMC-014 (12 months)	5.37
WCMC-015 (1 month)	10.9
WCMC-015 (3 months)	4.33
WCMC-017 (1 month)	10.9
WCMC-017 (3 month)	13.7
WCMC-020 (3 months)	11.7
WCMC-020 (12 months)	19.3
WCMC-021 (3 month)	3.67

Adverse Events

Time Frame	Up to 5 years and 6 months.
Arm/Group Title	All Patients
Arm/Group Description	Nilotinib at a dose of 300 mg P.O. twice a day (BID) daily Nilotinib
All Cause Mortality
	All Patients
	Affected / at Risk (%)	# Events
Total	0/16 (0%)
Serious Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	5/16 (31.3%)
Gastrointestinal disorders
Abdominal pain/vomiting/nausea	1/16 (6.3%)	1
Diarrheal illness	1/16 (6.3%)	1
Small bowel obstruction	1/16 (6.3%)	1
General disorders
Fever	1/16 (6.3%)	1
Intermittent left upper quadrant pain	1/16 (6.3%)	1
Pregnancy, puerperium and perinatal conditions
Pregnancy	1/16 (6.3%)	1
Skin and subcutaneous tissue disorders
Livido reticularis	1/16 (6.3%)	1
Other (Not Including Serious) Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	16/16 (100%)
Cardiac disorders
Bradycardia	1/16 (6.3%)	1
Coronary artery disease	1/16 (6.3%)	1
Palpitations	2/16 (12.5%)	6
Ear and labyrinth disorders
Ringing in ears	1/16 (6.3%)	1
Eye disorders
Conjunctiva injected	1/16 (6.3%)	2
Dry/Red eyes	5/16 (31.3%)	6
Periorbital edema	1/16 (6.3%)	1
Gastrointestinal disorders
Abdominal discomfort (pain or cramps)	5/16 (31.3%)	10
Appetite change	2/16 (12.5%)	2
Constipation	4/16 (25%)	5
Diarrhea	4/16 (25%)	6
Epigastric pain	2/16 (12.5%)	2
Gastric reflux syndrome	1/16 (6.3%)	1
Gastritis	1/16 (6.3%)	1
Gastroenteritis	1/16 (6.3%)	1
Heart burn	2/16 (12.5%)	2
Hemorrhoids	2/16 (12.5%)	2
Intermittent foul breath	1/16 (6.3%)	1
Nausea	3/16 (18.8%)	3
Vomiting	2/16 (12.5%)	2
General disorders
Chest pain/tightness	5/16 (31.3%)	8
Back pain	1/16 (6.3%)	1
Pain - knee	3/16 (18.8%)	3
Cold/cold symptoms	4/16 (25%)	5
Chipped tooth	1/16 (6.3%)	1
Nasal discharge	1/16 (6.3%)	1
Diabetes	1/16 (6.3%)	1
Dizziness/Lightheadedness	2/16 (12.5%)	2
Dog bite	1/16 (6.3%)	1
Dry mouth/perioral dryness	2/16 (12.5%)	2
Fall	1/16 (6.3%)	1
Fatigue	10/16 (62.5%)	14
Fever	3/16 (18.8%)	4
Generalized pain	3/16 (18.8%)	3
Hair darkening	1/16 (6.3%)	1
Hair thinning	1/16 (6.3%)	2
Hand/wrist pain	2/16 (12.5%)	2
Rib pain	2/16 (12.5%)	2
Lesion	2/16 (12.5%)	2
Night sweats	1/16 (6.3%)	1
Leg/Knee pain	3/16 (18.8%)	3
Palpable spleen	2/16 (12.5%)	2
Heel pain	1/16 (6.3%)	1
Neck pain	1/16 (6.3%)	1
Sensation of bugs crawling on left shoulder	1/16 (6.3%)	1
Splenic pain	1/16 (6.3%)	2
Stomach pain	2/16 (12.5%)	2
Swelling of upper lip	1/16 (6.3%)	1
Toothache	1/16 (6.3%)	1
Immune system disorders
Allergic rhinitis	1/16 (6.3%)	1
Seasonal allergies	1/16 (6.3%)	1
Infections and infestations
COVID/COVID Symptoms	2/16 (12.5%)	2
Kidney infection	1/16 (6.3%)	1
Stomach virus	1/16 (6.3%)	1
Strep throat	1/16 (6.3%)	1
Upper respiratory infection/symptoms	3/16 (18.8%)	4
Yeast infection	1/16 (6.3%)	1
Injury, poisoning and procedural complications
Bruising	2/16 (12.5%)	2
Pain at needle entry site	2/16 (12.5%)	2
Investigations
ALT elevated	4/16 (25%)	4
ALP elevated	5/16 (31.3%)	7
Amylase increased	2/16 (12.5%)	3
Anemia	11/16 (68.8%)	18
AST increased	3/16 (18.8%)	3
Basophilia	1/16 (6.3%)	1
Bilirubin elevated	2/16 (12.5%)	9
Elevated cholesterol	4/16 (25%)	4
Hyperglycemia	5/16 (31.3%)	19
Hyperlipidemia	3/16 (18.8%)	3
Elevated TSH	1/16 (6.3%)	1
Hematocrit decreased	1/16 (6.3%)	1
Hemoglobin decrease	1/16 (6.3%)	1
Hypocalcemia	4/16 (25%)	12
Hypoalbunemia	1/16 (6.3%)	1
Hypoglycemia	2/16 (12.5%)	2
Hyponatremia	2/16 (12.5%)	2
Hypophosphatemia	2/16 (12.5%)	2
Iron deficiency	1/16 (6.3%)	1
Leukocytosis	5/16 (31.3%)	5
Leukopenia	6/16 (37.5%)	11
Low MCV	1/16 (6.3%)	1
Lipase increased	2/16 (12.5%)	3
Lymphocyte count decreased	3/16 (18.8%)	9
Neutropenia	5/16 (31.3%)	8
Thrombocytopenia	10/16 (62.5%)	25
Platelet count increased	2/16 (12.5%)	2
Uric acid elevated	3/16 (18.8%)	3
Metabolism and nutrition disorders
Overweight	1/16 (6.3%)	1
Weight gain	2/16 (12.5%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	2/16 (12.5%)	3
Muscle cramp	1/16 (6.3%)	1
Myalgia	1/16 (6.3%)	1
Broken/fractured arm	1/16 (6.3%)	1
Tenderness behind knees	1/16 (6.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breasts cysts	1/16 (6.3%)	1
Neurofibroma	1/16 (6.3%)	1
Scalp nodule	1/16 (6.3%)	1
Nervous system disorders
Headaches	5/16 (31.3%)	6
Restless legs	1/16 (6.3%)	1
Psychiatric disorders
Anxiety	2/16 (12.5%)	2
Insomnia	1/16 (6.3%)	1
Renal and urinary disorders
Mid renal insufficiency	1/16 (6.3%)	1
Pain with urination	1/16 (6.3%)	1
Reproductive system and breast disorders
Missed period	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	6/16 (37.5%)	8
Dyspnea	4/16 (25%)	4
Sore throat	4/16 (25%)	5
Skin and subcutaneous tissue disorders
Acne	1/16 (6.3%)	1
Rash	7/16 (43.8%)	16
Dry skin	2/16 (12.5%)	2
Folliculitis	2/16 (12.5%)	4
Moles	1/16 (6.3%)	1
Pruritis	1/16 (6.3%)	1
Scalp irritation/itching	2/16 (12.5%)	2
Seborrheic Keratoses	1/16 (6.3%)	1
Vascular disorders
Hypertension	2/16 (12.5%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.