IST-CTI-MDS: Study of Clinical Efficacy and Safety of Tosedostat in MDS

• Sponsor: Weill Medical College of Cornell University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02452346
• Collaborator: CTI BioPharma (Industry)
• Enrollment: 12
• Location: 1
• Arm: 1
• Actual Duration (Months): 31.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Study WCMC IST-CTI-MDS evaluates the safety and tolerability of tosedostat in adult patients with pathologically confirmed MDS (< 20% blasts in bone marrow, peripheral blood, or both) by World Health Organization (WHO) classification after failure of hypomethylating agent-based therapy.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndrome	Drug: Tosedostat	Phase 2

Detailed Description

This is a single-center, open label, two-arm phase II study of clinical activity of tosedostat in adult patients with MDS who have failed prior hypomethylating agent-based therapy. Arm A is defined as Revised International Prognostic Scoring Systems (IPSS-R) very low, low, and intermediate disease. Arm B is defined as IPSS-R high or very high risk disease. The two arms are separate and will enroll simultaneously. The dose of tosedostat will be 120 mg once a day continuously for each 28 day treatment cycle. Patients will be assessed for disease response, on average, every two cycles as defined in the protocol. If patient has no response as defined by the protocol after two cycles, azacitidine 75 mg/m2 SC or IV for 5 days may be combined with tosedostat, at the investigator's discretion.The primary endpoint the study is to evaluate the safety and efficacy of tosedostat in two groups of patients with myelodysplastic syndrome who have relapsed after or are refractory or intolerant to azacitidine or decitabine. The primary endpoint for patients with IPSS-R very low, low and intermediate disease is transfusion independence and the primary endpoint for patients with high or very high risk disease is overall survival.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Clinical Study of the Clinical Efficacy and Safety of Tosedostat in Atients With Myelodysplastic Syndromes (MDS) After Failure of Hypomethylating Agent-Based Therapy
• Actual Study Start Date: Mar 20, 2015
• Actual Primary Completion Date: Oct 25, 2017
• Actual Study Completion Date: Oct 25, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: All Patients Tosedostat 120 mg PO once daily will be administered.	Drug: Tosedostat; 120 mg PO once daily continuously for each 28 day treatment cycle; Other Names: CHR-2797

Outcome Measures

Primary Outcome Measures

1. Over All Survival [from start of treatment until death, assessed up to a period of 3-4 years.]

   Survival following treatment to the date of death, assessed up to a period of 3-4 years.

Secondary Outcome Measures

1. Overall Response [Approximately 3 years]

   Overall response according to IWG 2006 criteira

2. One Year and Two Year Survival [from start of treatment to 1 year and 2 years post treatment initiation]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Able to understand and to provide written informed consent

2. At least 18 years of age with pathologically confirmed MDS (<20% blasts in bone marrow, peripheral blood, or both) within 6 weeks prior to screening by WHO classification

3. Must have received at least 4 cycles of decitabine-based or 6 cycles of azacitidine-based therapy and are either refractory to, relapsed after or intolerant to prior therapy with either agent.

• Primary failure/refractory: Stable or worsening disease after a minimum of 4 cycles of decitabine-based or 6 cycles of azacitidine-based therapy

• Secondary failure/relapse: Bone marrow blast count increase or loss of hematologic response after initial treatment response with hypomethylating agent-based therapy

• Intolerance: Intolerance of hypomethylating agent-based therapy regardless of number of cycles completed and clinical response

1. Progression (according to 2006 IWG criteria) at any time after initiation of subcutaneous or intravenous azacitidine or decitabine treatment per labeling during the past 2 years, defined as follows:

• For patients with <5% BMBL, ≥ 50% increase in BMBL to >5% BMBL

• For patients with 5-10% BMBL, ≥ 50% increase in BMBL to >10% BMBL

• For patients with 10-20% BMBL, ≥ 50% increase in BMBL to >20% BMBL

• For patients with 20-30% BMBL, ≥ 50% increase in BMBL to >30% BMBL

• Any of the following:

• ≥ 50% decrease from maximum remission/response levels in granulocytes or PLT

• Decrease in Hgb concentration by ≥2 g/dL

• Transfusion dependence, defined as administration of at least 4 RBC units in the past 8 weeks before Screening (patients must have Hgb values < 9 g/dL prior to transfusion to be considered), in the absence of another explanation.

1. Has failed to respond to, relapsed following, not eligible, or opted not to participate in BM transplantation

2. Patients with very low, low or intermediate risk MDS by the IPSS-R must be transfusion-dependent, with a packed red blood cell requirement of ≥ 2 units/month

3. Off azacitidine or decitabine for at least 2 weeks, off all other treatments for MDS for at least 4 weeks. Filgrastim (G-CSF) and EPO are allowed before and during the study as clinically indicated

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-3

5. Subjects must have adequate hepatic and renal function including the following:

• Total bilirubin ≤ 1.5 x upper limit of normal (in the absence of Gilbert's syndrome)

• AST and ALT ≤ 2.5 x upper limit of normal

• Serum creatinine ≤ 1.5 x upper limit of normal

1. Must have acceptable recovery from clinically significant non-hematologic toxicity after prior therapy.

2. Must have a life expectancy of at least 2 months

3. Screening left ventricular ejection fraction (LVEF) greater than 50% as documented by transthoracic echocardiogram (TTE)

4. Female subject of child-bearing potential and male subjects with female partners of reproductive potential must use acceptable contraceptive methods (hormonal or barrier method of birth control; abstinence) for the duration of time on study and continue to do so for a further 3 months after the end of tosedostat treatment. Should a female subject become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

5. Able to comply with all study procedures during the study including all visits and tests

6. Willing to adhere to the prohibitions and restrictions specified in this protocol

7. Patient must sign an informed consent form (ICF) indicating that s/he understands the purpose of and procedures required for the study and is willing to participate.

Exclusion Criteria:

1. Presence of AML (≥20% blasts in bone marrow, peripheral blood, or both)

2. Presence of serious illness, medical condition, or other medical history, involving the heart, kidney, liver, or other organ system, including abnormal laboratory parameters, which, in the opinion of the Investigator, would be likely to interfere with a subject's participation in the study or with the interpretation of the results.

3. Have known active central nervous system disease or active, uncontrolled, clinically significant infection(s)

4. Have other active malignancies (including other hematologic malignancies) or other malignancies within 12 months before enrollment, except non-melanoma skin cancer or cervical intraepithelial neoplasia

5. Are receiving any other investigational therapy or protocol-prohibited therapy

6. Have received previous treatment with tosedostat

7. Pregnant or breastfeeding females

8. Any prior or co-existing medical condition that in the Investigator's judgment will substantially increase the risk associated with the subject's participation in the study

9. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures

10. Significant* cardiovascular disease defined as:

• Active heart disease including myocardial infarction within 6 months prior to study entry

• Symptomatic coronary artery disease

• Uncontrolled or clinically significant arrhythmia, angina, congestive heart failure

• Presence of clinically significant valvular heart disease

• Presence of clinically significant conduction defect on screening ECG

• Uncontrolled hypertension (i.e., systolic BP >160mmHg, diastolic >90 mmHg in repeated measurements) despite adequate therapy

• Clinically significant atrial fibrillation * Grade 3/4 in the CTCAE v4.0 grading would generally be considered clinically significant, although this remains a judgment for the Investigator to make.

1. LVEF ≤ 50%

2. Baseline troponin I and b-type natriuretic peptide > Grade I

3. Prior exposure cardiotoxic agent, such as anthracycline, within 3 months of enrollment

4. Concomitant use of drugs that prolong QT/QTc interval except antibiotics, antifungals, and other antimicrobials used as standard of care for the treatment and prevention of infection and/or other such drugs clinically indicated for patient care. When use of concomitant medications with QT-prolonging potential is necessary, ECG must be repeated 4 hours post-dose on Day 1, on Day 3, and on Day 7, and as clinically indicated, relative to start of agent with QT-prolonging potential.

5. Gastrointestinal disorders that may interfere with absorption of drug

6. Active serious infection or sepsis

7. Clinically significant interstitial lung disease

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
• CTI BioPharma

Investigators

• Principal Investigator: Gail Roboz, MD, Weill Medical College of Cornell University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 6, 2016

More Information

Publications

None provided.

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT02452346
• Other Study ID Numbers: 1409015482
• First Posted: May 22, 2015
• Last Update Posted: Jun 12, 2018
• Last Verified: Jun 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Weill Medical College of Cornell University: MDS
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome; Tosedostat

Study Results

Participant Flow

Arm/Group Title	All Patients
Arm/Group Description	Tosedostat 120 mg PO once daily will be administered. Tosedostat: 120 mg PO once daily continuously for each 28 day treatment cycle
Period Title: Overall Study
STARTED	12
COMPLETED	3
NOT COMPLETED	9

Baseline Characteristics

Arm/Group Title	All Patients
Arm/Group Description	Tosedostat 120 mg PO once daily will be administered. Tosedostat: 120 mg PO once daily continuously for each 28 day treatment cycle
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 8.3%
>=65 years	11 91.7%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	72
Sex: Female, Male (Count of Participants)
Female	4 33.3%
Male	8 66.7%
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	0 0%
White	5 41.7%
More than one race	0 0%
Unknown or Not Reported	7 58.3%
Region of Enrollment (participants) [Number]
United States	12 100%

Outcome Measures

1. Primary Outcome

Title	Over All Survival
Description	Survival following treatment to the date of death, assessed up to a period of 3-4 years.
Time Frame	from start of treatment until death, assessed up to a period of 3-4 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	Tosedostat 120 mg PO once daily will be administered. Tosedostat: 120 mg PO once daily continuously for each 28 day treatment cycle
Measure Participants	12
Median (Full Range) [months]	15.9

2. Secondary Outcome

Title	Overall Response
Description	Overall response according to IWG 2006 criteira
Time Frame	Approximately 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	Tosedostat 120 mg PO once daily will be administered. Tosedostat: 120 mg PO once daily continuously for each 28 day treatment cycle
Measure Participants	12
Complete Remission	1 8.3%
Stable Disease	8 66.7%
Non-evaluable	3 25%

3. Secondary Outcome

Title	One Year and Two Year Survival
Time Frame	from start of treatment to 1 year and 2 years post treatment initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	Tosedostat 120 mg PO once daily will be administered. Tosedostat: 120 mg PO once daily continuously for each 28 day treatment cycle
Measure Participants	12
One year survival	8 66.7%
two year survival	4 33.3%

Adverse Events

Time Frame	The adverse event data was collected for a period of approx. 3 years from the date of enrollment.
Arm/Group Title	All Patients
Arm/Group Description	Tosedostat 120 mg PO once daily will be administered. Tosedostat: 120 mg PO once daily continuously for each 28 day treatment cycle
All Cause Mortality
	All Patients
	Affected / at Risk (%)	# Events
Total	9/12 (75%)
Serious Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	8/12 (66.7%)
Blood and lymphatic system disorders
Febrile neutropenia	2/12 (16.7%)
General disorders
Fever	1/12 (8.3%)
Infections and infestations
Sepsis	1/12 (8.3%)
Rash pustular	1/12 (8.3%)
Musculoskeletal and connective tissue disorders
Back pain	1/12 (8.3%)
Nervous system disorders
Other - Decline in performance status	1/12 (8.3%)
Syncope	1/12 (8.3%)
Other (Not Including Serious) Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Blood and lymphatic system disorders
Anemia	1/12 (8.3%)
Cardiac disorders
Atrial fibrillation	1/12 (8.3%)
Other - Demand ischemia	1/12 (8.3%)
Eye disorders
Blurred vision	1/12 (8.3%)
Other - left subconjunctival hemorrhage	1/12 (8.3%)
Gastrointestinal disorders
Diarrhea	5/12 (41.7%)
Toothache	2/12 (16.7%)
Abdominal pain	1/12 (8.3%)
Constipation	1/12 (8.3%)
Dry mouth	1/12 (8.3%)
Gastroenteritis	1/12 (8.3%)
Hemorrhoidal hemorrhage	1/12 (8.3%)
Hemorrhoids	1/12 (8.3%)
Mucositis	1/12 (8.3%)
Nausea	1/12 (8.3%)
Oral hemorrhage	1/12 (8.3%)
Vomiting	1/12 (8.3%)
General disorders
Fatigue	6/12 (50%)
Edema limbs	5/12 (41.7%)
Edema face	1/12 (8.3%)
Non-cardiac chest pain	1/12 (8.3%)
Immune system disorders
Allergic reaction	1/12 (8.3%)
Infections and infestations
Urinary tract infection	1/12 (8.3%)
Injury, poisoning and procedural complications
Bruising	5/12 (41.7%)
Fall	2/12 (16.7%)
Fracture	1/12 (8.3%)
Other - Lip excoriation	1/12 (8.3%)
Investigations
Other - BNP increased	7/12 (58.3%)
Electrocardiogram QT corrected interval prolonged	6/12 (50%)
Hypomagnesemia	4/12 (33.3%)
Alanine transferase increased	3/12 (25%)
Ejection fraction decreased	3/12 (25%)
Platelet count decreased	3/12 (25%)
GGT increased	2/12 (16.7%)
Neutrophil count decreased	2/12 (16.7%)
Alkaline phosphatase increased	1/12 (8.3%)
Aspartate aminotransferase increased	1/12 (8.3%)
Blood bilirubin increased	1/12 (8.3%)
Cardiac troponin I increased	1/12 (8.3%)
Creatinine increased	1/12 (8.3%)
INR increased	1/12 (8.3%)
Other - Ferritin increased	1/12 (8.3%)
Weight loss	1/12 (8.3%)
Metabolism and nutrition disorders
Hypokalemia	3/12 (25%)
Musculoskeletal and connective tissue disorders
Pain in extremity	2/12 (16.7%)
Back pain	1/12 (8.3%)
Flank pain	1/12 (8.3%)
Other - Muscle cramps	1/12 (8.3%)
Other - Muscle spasm	1/12 (8.3%)
Nervous system disorders
Dizziness	3/12 (25%)
Cognitive disturbance	1/12 (8.3%)
Lethargy	1/12 (8.3%)
Neuralgia	1/12 (8.3%)
Paresthesia, foot	1/12 (8.3%)
Psychiatric disorders
Insomnia	2/12 (16.7%)
Confusion	1/12 (8.3%)
Delirium	1/12 (8.3%)
Depression	1/12 (8.3%)
Other - Forgetfulness	1/12 (8.3%)
Renal and urinary disorders
Urinary incontinence	1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/12 (25%)
Cough	2/12 (16.7%)
Epistaxis	1/12 (8.3%)
Hiccups	1/12 (8.3%)
Hypoxia	1/12 (8.3%)
Other - Pneumonia	1/12 (8.3%)
Pulmonary edema	1/12 (8.3%)
Pulmonary hypertension	1/12 (8.3%)
Sore throat	1/12 (8.3%)
Skin and subcutaneous tissue disorders
Dry skin	3/12 (25%)
Urticaria	3/12 (25%)

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.