Phase I/II, Open-label, Multi-center, Two Part Dose-escalation, Safety, Pharmacokinetics (PK) and Efficacy Study of AZD4877 in Patients With Acute Myelogenous Leukemia (AML)

• Sponsor: AstraZeneca (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00486265
• Collaborator: (none)
• Enrollment: 47
• Locations: 4
• Duration (Months): 24
• Patients Per Site: 11.8
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The primary purpose of this study is to find out what the maximum tolerated dose is for an experimental drug called AZD4877 based on the side effects experienced by patients that receive AZD4877 on a daily times 3 schedule in acute myelogenous leukemia (AML).

For enrollment information see the Central Contact information below

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia	Drug: AZD4877	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II, Open-Label, Multi-Center, Two-Part Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of AZD4877 Administered on Days 1, 2 and 3 in Adult Patients With Recurrent or Refractory Acute Myelogenous Leukemia (AML) Excluding Promyelocytic Leukemia
• Study Start Date: Jul 1, 2007
• Actual Study Completion Date: Jul 1, 2009

Outcome Measures

Primary Outcome Measures

1. To Identify a Maximum Tolerated Dose (MTD) of AZD4877 by Assessment of the Incidence of Dose-limiting Toxicities (DLTs) [Dose-limiting toxicities (DLTs) are evaluated during the first induction treatment course administered during the initial 15-day treatment period.]

   To identify a maximum tolerated dose (MTD) of AZD4877 by assessment of the incidence of dose-limiting toxicities (DLTs)

2. To Assess the Effect of AZD4877 on the Rate of Complete Remission (CR) [Response is evaluated after a maximum of 2 courses of induction therapy.]

   Marrow response is assessed by modified Cheson criteria for Acute Myelogenous Leukemia (AML). Possible outcomes for marrow response are CR (Complete Remission), CRi (Complete Remission with incomplete blood count recovery), PR (Partial Remission), and treatment failure.

3. To Determine the PK Profile of AZD4877 [ Time Frame: Daily x 3 Schedule ] [PK samples are collected on Days 1, 2, 3, 24 and 48 hours following the end of Day 3 AZD4877 infusion and Day 8.]

   Maximum plasma concentration, Cmax

Secondary Outcome Measures

1. To Assess the Effect of AZD4877 on Rate and Duration of CR, CRi, PR and Overall Response (CR,CRi, or PR) [Response is evaluated after a maximum of 2 courses of induction therapy.]

   Marrow response is assessed by modified Cheson criteria for Acute Myelogenous Leukemia (AML). Possible outcomes for marrow response are CR (Complete Remission), CRi (Complete Remission with incomplete blood count recovery), PR (Partial Remission), and treatment failure.

2. To Evaluate the Safety and Tolerability of AZD4877 on a Daily x 3 Schedule by Assessment of Adverse Events, Non-hematologic Labs and Vital Signs [Patients were followed for safety from the date of first dose of AZD4877 up to 30-days after the last administration of AZD4877, where possible.]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Part A: Relapsed or refractory leukemia for which no standard therapies are anticipated to result in a durable remission

• Part B: AML who have had no more than two prior relapses or failed to achieve remission after at least one induction treatment.

• Patients with prior allogeneic transplants who remain clinically stable for ≥2 weeks or more off immunosuppressive therapy

Exclusion Criteria:

• Promyelocytic acute myelogenous leukemia

• Prior allogeneic transplant requiring immunosuppressive therapy or treating physician does not consider patient to be a candidate for allogeneic transplantation.

• Liver injury

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Chicago	Illinois	United States
2	Research Site	Houston	Texas	United States
3	Research Site	San Antonio	Texas	United States
4	Research Site	Toronto	Ontario	Canada

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Gregory A Curt, MD, AstraZeneca

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00486265
• Other Study ID Numbers: D2782C00007
• First Posted: Jun 14, 2007
• Last Update Posted: Dec 21, 2010
• Last Verified: Jul 1, 2010

• Keywords provided by , ,: Phase I; Phase II; acute myelogenous leukemia; AML; cancer
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute

Study Results

Participant Flow

Recruitment Details	Participants were recruited at 4 study sites in the United States and 1 study site in Canada between July 2007 and February 2009 [Part A] and between March 2009 and July 2009 [Part B].
Pre-assignment Detail	Following enrolment there was screening period of up to 28 days, after which if all inclusion/exclusion criteria were met, patients were dosed with AZD4877

Arm/Group Title	AZD4877
Arm/Group Description	AZD4877 [ Time Frame: administered on days 1,2 and 3]
Period Title: Overall Study
STARTED	9
COMPLETED	0
NOT COMPLETED	9

Baseline Characteristics

Arm/Group Title	AZD4877
Arm/Group Description	AZD4877 [ Time Frame: administered on days 1,2 and 3]
Overall Participants	9
Age, Customized (Number) [Number]
< 18 Years	0 0%
>=18 - < 65 Years	6 66.7%
>=65 - < 75 Yrs	1 11.1%
>=75 Yrs	2 22.2%
Sex: Female, Male (Count of Participants)
Female	4 44.4%
Male	5 55.6%
Race/Ethnicity, Customized (Number) [Number]
White	8 88.9%
Black or African American	1 11.1%

Outcome Measures

1. Primary Outcome

Title	To Identify a Maximum Tolerated Dose (MTD) of AZD4877 by Assessment of the Incidence of Dose-limiting Toxicities (DLTs)
Description	To identify a maximum tolerated dose (MTD) of AZD4877 by assessment of the incidence of dose-limiting toxicities (DLTs)
Time Frame	Dose-limiting toxicities (DLTs) are evaluated during the first induction treatment course administered during the initial 15-day treatment period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

2. Primary Outcome

Title	To Assess the Effect of AZD4877 on the Rate of Complete Remission (CR)
Description	Marrow response is assessed by modified Cheson criteria for Acute Myelogenous Leukemia (AML). Possible outcomes for marrow response are CR (Complete Remission), CRi (Complete Remission with incomplete blood count recovery), PR (Partial Remission), and treatment failure.
Time Frame	Response is evaluated after a maximum of 2 courses of induction therapy.

Outcome Measure Data

Analysis Population Description

8 of 9 patients in Part B were evaluable for response following a maximum of 2 courses of induction therapy.

Arm/Group Title	AZD4877
Arm/Group Description	AZD4877 [ Time Frame: administered on days 1,2 and 3]
Measure Participants	8
Number [Participants]	0 0%

3. Primary Outcome

Title	To Determine the PK Profile of AZD4877 [ Time Frame: Daily x 3 Schedule ]
Description	Maximum plasma concentration, Cmax
Time Frame	PK samples are collected on Days 1, 2, 3, 24 and 48 hours following the end of Day 3 AZD4877 infusion and Day 8.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	To Assess the Effect of AZD4877 on Rate and Duration of CR, CRi, PR and Overall Response (CR,CRi, or PR)
Description	Marrow response is assessed by modified Cheson criteria for Acute Myelogenous Leukemia (AML). Possible outcomes for marrow response are CR (Complete Remission), CRi (Complete Remission with incomplete blood count recovery), PR (Partial Remission), and treatment failure.
Time Frame	Response is evaluated after a maximum of 2 courses of induction therapy.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	To Evaluate the Safety and Tolerability of AZD4877 on a Daily x 3 Schedule by Assessment of Adverse Events, Non-hematologic Labs and Vital Signs
Time Frame	Patients were followed for safety from the date of first dose of AZD4877 up to 30-days after the last administration of AZD4877, where possible.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	AZD4877
Arm/Group Description	AZD4877 [ Time Frame: administered on days 1,2 and 3]
All Cause Mortality
	AZD4877
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	AZD4877
	Affected / at Risk (%)	# Events
Total	3/9 (33.3%)
General disorders
Mucosal Inflammation	3/9 (33.3%)
Skin and subcutaneous tissue disorders
Stevens-Johnson Syndrome	1/9 (11.1%)
Other (Not Including Serious) Adverse Events
	AZD4877
	Affected / at Risk (%)	# Events
Total	9/9 (100%)
Blood and lymphatic system disorders
Anaemia	1/9 (11.1%)
Leukopenia	1/9 (11.1%)
Neutropenia	1/9 (11.1%)
Thrombocytopenia	1/9 (11.1%)
Cardiac disorders
Sinus Tachycardia	1/9 (11.1%)
Congenital, familial and genetic disorders
Hypophosphatasia	1/9 (11.1%)
Ear and labyrinth disorders
Ear Pain	1/9 (11.1%)
Eye disorders
Dry Eye	1/9 (11.1%)
Gastrointestinal disorders
Constipation	3/9 (33.3%)
Diarrhoea	3/9 (33.3%)
Nausea	3/9 (33.3%)
Abdominal Pain	1/9 (11.1%)
Dysphagia	1/9 (11.1%)
General disorders
Mucosal Inflammation	6/9 (66.7%)
Fatigue	3/9 (33.3%)
Oedema Peripheral	2/9 (22.2%)
Asthenia	1/9 (11.1%)
Chills	1/9 (11.1%)
Oedema	1/9 (11.1%)
Hepatobiliary disorders
Hepatic Cyst	1/9 (11.1%)
Hepatic Lesion	1/9 (11.1%)
Hyperbilirubinaemia	1/9 (11.1%)
Infections and infestations
Ear Infection	1/9 (11.1%)
Pneumonia	1/9 (11.1%)
Injury, poisoning and procedural complications
Limb Injury	1/9 (11.1%)
Transfusion Reaction	1/9 (11.1%)
Investigations
Activated Partial Thromboplastin Time Prolonged	1/9 (11.1%)
Alanine Aminotransferase Increased	1/9 (11.1%)
Aspartate Aminotransferase Increased	1/9 (11.1%)
Blood Creatinine Increased	1/9 (11.1%)
Blood Phosphorus Increased	1/9 (11.1%)
Blood Pressure Orthostatic Decreased	1/9 (11.1%)
Transaminases Increased	1/9 (11.1%)
Metabolism and nutrition disorders
Hypokalaemia	5/9 (55.6%)
Hypomagnesaemia	5/9 (55.6%)
Hypocalcaemia	4/9 (44.4%)
Hypoalbuminaemia	3/9 (33.3%)
Hyponatraemia	3/9 (33.3%)
Decreased Appetite	2/9 (22.2%)
Hyperglycaemia	2/9 (22.2%)
Hyperuricaemia	2/9 (22.2%)
Hypophosphataemia	2/9 (22.2%)
Hyperphosphataemia	1/9 (11.1%)
Musculoskeletal and connective tissue disorders
Back Pain	1/9 (11.1%)
Pain In Extremity	1/9 (11.1%)
Pain In Jaw	1/9 (11.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemangioma Of Liver	1/9 (11.1%)
Nervous system disorders
Headache	3/9 (33.3%)
Neuropathy Peripheral	2/9 (22.2%)
Dizziness	1/9 (11.1%)
Syncope	1/9 (11.1%)
Psychiatric disorders
Insomnia	2/9 (22.2%)
Depression	1/9 (11.1%)
Mood Altered	1/9 (11.1%)
Renal and urinary disorders
Dysuria	1/9 (11.1%)
Haematuria	1/9 (11.1%)
Proteinuria	1/9 (11.1%)
Renal Cyst	1/9 (11.1%)
Respiratory, thoracic and mediastinal disorders
Cough	2/9 (22.2%)
Dyspnoea	1/9 (11.1%)
Oropharyngeal Pain	1/9 (11.1%)
Pulmonary Oedema	1/9 (11.1%)
Skin and subcutaneous tissue disorders
Rash	2/9 (22.2%)
Dry Skin	1/9 (11.1%)
Skin Irritation	1/9 (11.1%)
Stevens-Johnson Syndrome	1/9 (11.1%)
Vascular disorders
Hypotension	2/9 (22.2%)

Limitations/Caveats

On 16 June 2009, the study was terminated for a lack of efficacy. None of the 8 patients had experienced CR or CRi. The secondary efficacy outcome measures were not evaluated due to early termination and small number of participants.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The PI agrees to provide a copy of the publication to AZ for review at least 60 days in advance of submission for publication. Investigators in multicenter (MC) studies agree to postpone MC publications until the earlier of the date of the first AZ authorized MC publication or a period up to 18 months from study completion at all sites. AZ has the right to request delays: up to 60 days for confidential information, and an additional 90 days to protect intellectual property.