An Open Label Phase II Pharmacokinetic and Pharmacodynamic Assessment of the Potential for QTc Prolongation Following First Induction Treatment With CPX-351 (Cytarabine:Daunorubicin) Liposome Injection in Acute Leukemias and MDS Patients

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02238925
• Collaborator: (none)
• Enrollment: 26
• Locations: 5
• Arm: 1
• Duration (Months): 18
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the effects of CPX-351 on cardiac repolarization, assess plasma drug levels, asses serum copper levels, and assess drug levels in urine.

Efficacy and Safety will be assessed in all patients enrolled to the study.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia (AML); Acute Lymphoblastic Leukemia (ALL); Myelodysplastic Syndrome (MDS)	Drug: CPX-351	Phase 2

Detailed Description

This study is an open-label, single-arm, Phase II, PK and pharmacodynamic (PD) trial of CPX-351 in patients with documented acute leukemia (AML or ALL) or MDS (IPSS score ≥ 1.5) and suitable for treatment with intensive chemotherapy. Each patient will be screened for hepatic impairment. Hepatic impairment will be assessed using the Child-Pugh system and only patients with a Child-Pugh score <7 points will be eligible for this study. Patients will receive up to two inductions and four consolidation courses. Patients will be monitored for safety (early deaths, adverse events, metabolic changes, etc.) and efficacy (response for AML, ALL, and MDS) while on the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Phase II Pharmacokinetic and Pharmacodynamic Assessment of the Potential for QTc Prolongation Following First Induction Treatment With CPX-351 (Cytarabine:Daunorubicin) Liposome Injection in Acute Leukemias and MDS Patients
• Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: CPX-351 Single Arm Study (Patients may receive up to 2 Inductions and 4 Consolidations): Induction 1: CPX-351 will be given intravenously at 100units/m2 on days 1, 3, and 5 over a 90 minute infusion. Induction 2: CPX-351 will be given intravenously at 100units/m2 on days 1 and 3 over a 90 minute infusion. Consolidations 1-4: CPX-351 will be given intravenously at 65units/m2 on days 1 and 3 over a 90 minute infusion.

Drug: CPX-351

Outcome Measures

Primary Outcome Measures

1. Effect of CPX-351 on Cardiac Ventricular Repolarization (QTcF) [21 days]

   Time-matched QTcF Changes From Baseline after the start of first infusion

Secondary Outcome Measures

1. Serum Copper Levels Change From Baseline [During 1st induction (up to 5 days)]

   Change from Baseline to Induction 1, Day 5

2. Complete Response Rate [Following 1st induction, following 2nd induction if applicable]

3. Tmax [Induction 1, Day 5]

4. Cmax [Induction 1, Day 5]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ability to understand and voluntarily sign an informed consent form

• Age ≥ 18 to ≤ 80 years at the time of signing the informed consent form

• Life expectancy of at least 3 months

• Pathological confirmation by bone marrow documenting the following:

• Newly Diagnosed De novo AML according to WHO criteria except for Acute Promyelocytic Leukemia or patients with known favorable cytogenetics (see exclusion)

• Newly Diagnosed Secondary AML age <60 years and ≥76 to 80 years, defined as having a history of an antecedent hematologic disorder (myelodysplastic syndromes [MDS], myeloproliferative disease [MPD]or history of cytotoxic treatment for non-hematologic malignancy)

• Patients with relapsed/refractory AML regardless of cytogenetic risk

• Patients with relapsed/refractory ALL

• Patients with MDS (IPSS score ≥ 1.5)

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2

• Able to adhere to the study visit schedule and other protocol requirements

• Laboratory values fulfilling the following:

• Serum Creatinine ≤ 2.0mg/dL

• Hepatic function with a score of < 7 points according to the Child-Pugh System

• Serum alanine aminotransferase or aspartate aminotransferase < 3 times the ULN. Note: If elevated liver enzymes are related to disease; contact medical monitor to discuss.

• Cardiac ejection fraction ≥50% by ECHO or MUGA

• Screening and Baseline QTcF (Fridericia's) less than 470 msec

• Patients with second malignancies in remission may be eligible if there is clinical evidence of disease stability for a period of greater than 6 months off cytotoxic chemotherapy, documented by imaging, tumor marker studies, etc., at screening. Patients maintained on long-term non-chemotherapy treatment, e.g., hormonal therapy, are eligible.

• All men and women must agree to practice effective contraception during the study period if not otherwise documented to be infertile.

Exclusion Criteria:

• Patients eligible for participation in Study CLTR0310-301 (Phase III study of CPX-351 NCT01696084) or who have already participated in that study are not eligible for this study.

• Patients taking medications known to prolong the QTc interval directly or that interact pharmacodynamically with medicines to prolong the QTc interval.

• Rhythm abnormalities (other than sinus bradycardia with HR < 50 bpm)

• AV block (other than 1o AV Block with PR > 200 msec)

• Bundle branch block or QRS ≥ 120 msec

• Abnormal T wave morphology (other than slight flattening)

• Pathological U waves

• Other QRS or T/U morphology preventing accurate determination of QT interval

• Patients with unexplained syncope, history of or known risk factors for torsade des pointes, including congenital long QT syndrome, or family history of LQTS.

• Patients with history of and/or current evidence of myocardial impairment (e.g. cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (Class III or IV staging)

• Newly diagnosed patients with Acute promyelocytic leukemia [t(15;17)] or favorable cytogenetics, including t(8;21) or inv16

• Clinical evidence of active CNS leukemic involvement

• Chemotherapy or other investigational anticancer therapeutic drugs within 1 week prior to study entry unless AEs have resolved and there is no interference with the assessment of efficacy or safety; in the event of rapidly proliferative disease, however, the use of hydroxyurea is permitted up to 12 hours before study entry. Patients with prior bone marrow or stem cell transplant, considered for inclusion, should be discussed with the medical monitor first.

• Any serious medical condition or psychiatric illness that would prevent the patient from providing informed consent

• Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent)

• Active or uncontrolled infection. Patients with any infection receiving treatment (antibiotic, antifungal or antiviral treatment) may be entered into the study but must be afebrile and hemodynamically stable for ≥72 hrs. Patients with fevers believed to be due to leukemia or MDS are eligible provided a thorough infection work-up is negative and the patient is clinically and hemodynamically stable.

• Pregnant or lactating women

• Hypersensitivity to cytarabine, daunorubicin or liposomal products

• History of Wilson's disease or other copper-related metabolic disorder

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Franciscan Saint Francis Health	Indianapolis	Indiana	United States	46237
2	University of Kansas Cancer Center	Westwood	Kansas	United States	66205
3	Oregon Health & Science University	Portland	Oregon	United States	97239
4	Medical University of South Carolina	Charleston	South Carolina	United States	29425
5	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02238925
• Other Study ID Numbers: CLTR0310-206
• First Posted: Sep 12, 2014
• Last Update Posted: Nov 30, 2017
• Last Verified: Oct 1, 2017

• Keywords provided by Jazz Pharmaceuticals: Newly Diagnosed AML; Secondary AML; Relapsed/Refractory AML; Relapsed/Refractory ALL; MDS
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid, Acute; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes

Study Results

Participant Flow

Arm/Group Title	CPX-351
Arm/Group Description	Single Arm Study (Patients may receive up to 2 Inductions and up to 4 Consolidations): Induction 1: CPX-351 will be given intravenously at 100units/m2 on days 1, 3, and 5 over a 90 minute infusion. Induction 2: CPX-351 will be given intravenously at 100units/m2 on days 1 and 3 over a 90 minute infusion. Consolidations: CPX-351 will be given intravenously at 65units/m2 on days 1 and 3 over a 90 minute infusion. CPX-351
Period Title: Overall Study
STARTED	26
COMPLETED	1
NOT COMPLETED	25

Baseline Characteristics

Arm/Group Title	CPX-351
Arm/Group Description	Single Arm Study (Patients may receive up to 2 Inductions and up to 4 Consolidations): Induction 1: CPX-351 will be given intravenously at 100units/m2 on days 1, 3, and 5 over a 90 minute infusion. Induction 2: CPX-351 will be given intravenously at 100units/m2 on days 1 and 3 over a 90 minute infusion. Consolidations: CPX-351 will be given intravenously at 65units/m2 on days 1 and 3 over a 90 minute infusion. CPX-351
Overall Participants	26
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.2 (9.31)
Sex: Female, Male (Count of Participants)
Female	12 46.2%
Male	14 53.8%

Outcome Measures

1. Primary Outcome

Title	Effect of CPX-351 on Cardiac Ventricular Repolarization (QTcF)
Description	Time-matched QTcF Changes From Baseline after the start of first infusion
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

All subjects who received any dose of study drug and had at least 1 time-matched change from baseline in ECG parameters.

Arm/Group Title	CPX-351
Arm/Group Description	Single Arm Study (Patients may receive up to 2 Inductions and up to 4 Consolidations): Induction 1: CPX-351 will be given intravenously at 100units/m2 on days 1, 3, and 5 over a 90 minute infusion. Induction 2: CPX-351 will be given intravenously at 100units/m2 on days 1 and 3 over a 90 minute infusion. Consolidations: CPX-351 will be given intravenously at 65units/m2 on days 1 and 3 over a 90 minute infusion. CPX-351
Measure Participants	26
Time-point 0.75 h	0.6 (15.13)
Time-point 1.5 h	-1.2 (13.30)
Time-point 2 h	4.3 (15.96)
Time-point 3 h	5.3 (15.17)
Time-point 4 h	8.0 (11.69)
Time-point 6 h	-0.1 (11.24)
Time-point 8 h	4.8 (8.52)
Time-point 12 h	-2.3 (10.43)
Time-point 24 h	-6.2 (13.91)

2. Secondary Outcome

Title	Serum Copper Levels Change From Baseline
Description	Change from Baseline to Induction 1, Day 5
Time Frame	During 1st induction (up to 5 days)

Outcome Measure Data

Analysis Population Description

All subjects who received at least 1 dose of study drug and copper data were collected.

Arm/Group Title	CPX-351
Arm/Group Description	Single Arm Study (Patients may receive up to 2 Inductions and up to 4 Consolidations): Induction 1: CPX-351 will be given intravenously at 100units/m2 on days 1, 3, and 5 over a 90 minute infusion. Induction 2: CPX-351 will be given intravenously at 100units/m2 on days 1 and 3 over a 90 minute infusion. Consolidations: CPX-351 will be given intravenously at 65units/m2 on days 1 and 3 over a 90 minute infusion. CPX-351
Measure Participants	24
Mean (Standard Deviation) [μg/dL]	64.95 (51.119)

3. Secondary Outcome

Title	Complete Response Rate
Time Frame	Following 1st induction, following 2nd induction if applicable

Outcome Measure Data

Analysis Population Description

Efficacy population: All subjects who received at least 1 dose of study drug.

Arm/Group Title	CPX-351
Arm/Group Description	Single Arm Study (Patients may receive up to 2 Inductions and up to 4 Consolidations): Induction 1: CPX-351 will be given intravenously at 100units/m2 on days 1, 3, and 5 over a 90 minute infusion. Induction 2: CPX-351 will be given intravenously at 100units/m2 on days 1 and 3 over a 90 minute infusion. Consolidations: CPX-351 will be given intravenously at 65units/m2 on days 1 and 3 over a 90 minute infusion. CPX-351
Measure Participants	26
Count of Participants [Participants]	8 30.8%

4. Secondary Outcome

Title	Tmax
Time Frame	Induction 1, Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CPX-351
Arm/Group Description	Single Arm Study (Patients may receive up to 2 Inductions and up to 4 Consolidations): Induction 1: CPX-351 will be given intravenously at 100units/m2 on days 1, 3, and 5 over a 90 minute infusion. Induction 2: CPX-351 will be given intravenously at 100units/m2 on days 1 and 3 over a 90 minute infusion. Consolidations: CPX-351 will be given intravenously at 65units/m2 on days 1 and 3 over a 90 minute infusion. CPX-351
Measure Participants	26
Cytarabine	2.00
Ara-U	8.00
Daunorubicin	2.00
Daunorubicinol	26.00

5. Secondary Outcome

Title	Cmax
Time Frame	Induction 1, Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CPX-351
Arm/Group Description	Single Arm Study (Patients may receive up to 2 Inductions and up to 4 Consolidations): Induction 1: CPX-351 will be given intravenously at 100units/m2 on days 1, 3, and 5 over a 90 minute infusion. Induction 2: CPX-351 will be given intravenously at 100units/m2 on days 1 and 3 over a 90 minute infusion. Consolidations: CPX-351 will be given intravenously at 65units/m2 on days 1 and 3 over a 90 minute infusion. CPX-351
Measure Participants	26
Cytarabine	62200 (20900)
Ara-U	1240 (252)
Daunorubicin	26000 (8510)
Daunorubicinol	147 (52.3)

Adverse Events

Time Frame	Adverse events were recorded from the start of infusion to the last day of the study period, whereas Serious Adverse Events were reported from the start of infusion until 30 days after completion of the study period.
Adverse Event Reporting Description	The Safety population included subjects receiving at least 1 dose of study drug.
Arm/Group Title	CPX-351
Arm/Group Description	Single Arm Study (Patients may receive up to 2 Inductions and up to 4 Consolidations): Induction 1: CPX-351 will be given intravenously at 100units/m2 on days 1, 3, and 5 over a 90 minute infusion. Induction 2: CPX-351 will be given intravenously at 100units/m2 on days 1 and 3 over a 90 minute infusion. Consolidations: CPX-351 will be given intravenously at 65units/m2 on days 1 and 3 over a 90 minute infusion. CPX-351
All Cause Mortality
	CPX-351
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	CPX-351
	Affected / at Risk (%)	# Events
Total	8/26 (30.8%)
Blood and lymphatic system disorders
Febrile Neutropenia	7/26 (26.9%)
Gastrointestinal disorders
Ileus	1/26 (3.8%)
Infections and infestations
Catheter Site Infection	1/26 (3.8%)
Lung Infection	1/26 (3.8%)
Meningitis Bacterial	1/26 (3.8%)
Pathogen Resistance	1/26 (3.8%)
Pneumonia	1/26 (3.8%)
Pulmonary Mycosis	1/26 (3.8%)
Sepsis	1/26 (3.8%)
Investigations
Ejection Fraction Decreased	1/26 (3.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute Myeloid Leukamia Recurrent	1/26 (3.8%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure	1/26 (3.8%)
Hypoxia	1/26 (3.8%)
Other (Not Including Serious) Adverse Events
	CPX-351
	Affected / at Risk (%)	# Events
Total	26/26 (100%)
Blood and lymphatic system disorders
Febrile Neutropenia	17/26 (65.4%)
Cardiac disorders
Sinus Tachycardia	5/26 (19.2%)
Tachycardia	4/26 (15.4%)
Eye disorders
Blepharospasm	2/26 (7.7%)
Conjunctival Haemorrhage	2/26 (7.7%)
Dry Eye	2/26 (7.7%)
Vitreous Floaters	2/26 (7.7%)
Gastrointestinal disorders
Nausea	14/26 (53.8%)
Diarrhoea	12/26 (46.2%)
Constipation	11/26 (42.3%)
Vomiting	10/26 (38.5%)
Abdominal Pain	6/26 (23.1%)
Gingival Bleeding	4/26 (15.4%)
Abdominal Pain Lower	3/26 (11.5%)
Dysphagia	3/26 (11.5%)
Faecal Incontinence	3/26 (11.5%)
Stomatitis	3/26 (11.5%)
Cheilitis	2/26 (7.7%)
Gastrooesophageal Reflux Disease	2/26 (7.7%)
Gingival Pain	2/26 (7.7%)
Haemorrhoids	2/26 (7.7%)
General disorders
Fatigue	14/26 (53.8%)
Oedema Peripheral	10/26 (38.5%)
Chills	7/26 (26.9%)
Pyrexia	6/26 (23.1%)
Gait Disturbance	3/26 (11.5%)
Mucosal Inflammation	3/26 (11.5%)
Non-Cardiac Chest Pain	3/26 (11.5%)
Nodule	2/26 (7.7%)
Infections and infestations
Bacteraemia	3/26 (11.5%)
Sinusitis	3/26 (11.5%)
Cellulitis	2/26 (7.7%)
Clostridium Difficile Colitis	2/26 (7.7%)
Device Related Infection	2/26 (7.7%)
Folliculitis	2/26 (7.7%)
Staphylococcal Bacteraemia	2/26 (7.7%)
Injury, poisoning and procedural complications
Contusion	3/26 (11.5%)
Excoriation	2/26 (7.7%)
Investigations
Human Rhinovirus Test Positive	2/26 (7.7%)
Viral Test Positive	2/26 (7.7%)
Weight Decreased	2/26 (7.7%)
Weight Increased	2/26 (7.7%)
Metabolism and nutrition disorders
Decreased Appetite	12/26 (46.2%)
Fluid Overload	3/26 (11.5%)
Fluid Retention	2/26 (7.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	6/26 (23.1%)
Back Pain	6/26 (23.1%)
Neck Pain	5/26 (19.2%)
Muscular Weakness	3/26 (11.5%)
Musculoskeletal Pain	3/26 (11.5%)
Pain In Jaw	3/26 (11.5%)
Joint Swelling	2/26 (7.7%)
Musculoskeletal Chest Pain	2/26 (7.7%)
Musculoskeletal Stiffness	2/26 (7.7%)
Myalgia	2/26 (7.7%)
Pain In Extremity	2/26 (7.7%)
Nervous system disorders
Headache	11/26 (42.3%)
Dizziness	5/26 (19.2%)
Dizziness Postural	3/26 (11.5%)
Tremor	3/26 (11.5%)
Ataxia	2/26 (7.7%)
Hypoaesthesia	2/26 (7.7%)
Sinus Headache	2/26 (7.7%)
Psychiatric disorders
Insomnia	11/26 (42.3%)
Confusional State	6/26 (23.1%)
Depression	4/26 (15.4%)
Agitation	3/26 (11.5%)
Anxiety	2/26 (7.7%)
Delirium	2/26 (7.7%)
Sleep Disorder	2/26 (7.7%)
Renal and urinary disorders
Chromaturia	4/26 (15.4%)
Pollakiuria	4/26 (15.4%)
Urinary Incontinence	4/26 (15.4%)
Haematuria	3/26 (11.5%)
Dysuria	2/26 (7.7%)
Micturition Urgency	2/26 (7.7%)
Urinary Retention	2/26 (7.7%)
Respiratory, thoracic and mediastinal disorders
Cough	9/26 (34.6%)
Hypoxia	7/26 (26.9%)
Oropharyngeal Pain	7/26 (26.9%)
Epistaxis	6/26 (23.1%)
Dyspnoea	5/26 (19.2%)
Atelectasis	4/26 (15.4%)
Pleural Effusion	4/26 (15.4%)
Pulmonary Oedema	4/26 (15.4%)
Dysphonia	3/26 (11.5%)
Nasal Congestion	3/26 (11.5%)
Rales	3/26 (11.5%)
Wheezing	3/26 (11.5%)
Haemoptysis	2/26 (7.7%)
Pneumonitis	2/26 (7.7%)
Productive Cough	2/26 (7.7%)
Pulmonary Mass	2/26 (7.7%)
Rhinorrhoea	2/26 (7.7%)
Upper-Airway Cough Syndrome	2/26 (7.7%)
Skin and subcutaneous tissue disorders
Rash Maculo-Papular	5/26 (19.2%)
Erythema	4/26 (15.4%)
Petechiae	4/26 (15.4%)
Pruritus	4/26 (15.4%)
Rash	4/26 (15.4%)
Hyperhidrosis	3/26 (11.5%)
Rash Erythematous	3/26 (11.5%)
Rash Papular	3/26 (11.5%)
Rash Pruritic	3/26 (11.5%)
Blood Blister	2/26 (7.7%)
Erythema Multiforme	2/26 (7.7%)
Purpura	2/26 (7.7%)
Rash Macular	2/26 (7.7%)
Skin Mass	2/26 (7.7%)
Vascular disorders
Hypotension	8/26 (30.8%)
Hypertension	4/26 (15.4%)
Flushing	2/26 (7.7%)
Haematoma	2/26 (7.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.