Cytarabine With or Without SCH 900776 in Treating Adult Patients With Relapsed Acute Myeloid Leukemia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01870596
• Collaborator: (none)
• Enrollment: 32
• Locations: 5
• Arms: 2
• Duration (Months): 19
• Patients Per Site: 6.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This randomized phase II trial studies how well cytarabine with or without SCH 900776 works in treating adult patients with relapsed acute myeloid leukemia. Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or stopping them from dividing. SCH 900776 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether cytarabine is more effective with or without SCH 900776 in treating acute myeloid leukemia.

Condition or Disease	Intervention/Treatment	Phase
Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia	Drug: Cytarabine; Drug: CHK1 Inhibitor SCH 900776; Other: Laboratory Biomarker Analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To compare the rates of complete remission (CR) plus CR with incomplete recovery (CRi) achieved with cytosine arabinoside (ara-C) (cytarabine) plus the checkpoint kinase 1 (CHK1) inhibitor MK-8776 (Chk1 inhibitor SCH 900776) vs. ara-C alone for adults (ages 18-75) with relapsed acute myelogenous leukemia (AML).

SECONDARY OBJECTIVES:

1. To evaluate and compare the toxicities of ara-C + MK-8776 vs. ara-C alone. II. To determine the disease free and overall survival of those achieving response to treatment.

2. To determine the impact of MK-8776 on AML blast cell deoxyribonucleic acid (DNA) repair protein expression profiles and correlate the expression profiles with CR/CRi in response to ara-C + MK-8776 vs. ara-C alone.

3. To evaluate and compare the amount of DNA damage induced in AML blasts by ara-C + MK-8776 vs. ara-C.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive cytarabine intravenously (IV) continuously over 72 hours on days 1-3 and 10-12 and Chk1 inhibitor SCH 900776 IV over 30 minutes on days 2, 3, 11, and 12.

ARM B: Patients receive cytarabine as in Arm A.

In both arms, courses may repeat every 28 days.

After completion of study treatment, patients are followed up periodically.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Trial of Timed Sequential Cytosine Arabinoside (Ara-C) With and Without the Checkpoint Kinase 1 (CHK1) Inhibitor MK-8776 in Adults With Relapsed AML
• Study Start Date: May 1, 2013
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (cytarabine, Chk1 inhibitor SCH 900776) Patients receive cytarabine IV continuously over 72 hours on days 1-3 and 10-12 and Chk1 inhibitor SCH 900776 IV over 30 minutes on days 2, 3, 11, and 12.	Drug: Cytarabine; Given IV; Other Names: CHX-3311 U-19920 ; Drug: CHK1 Inhibitor SCH 900776; Given IV; Other Names: SCH 900776 ; Other: Laboratory Biomarker Analysis; Correlative studies
Active Comparator: Arm B (cytarabine) Patients receive cytarabine as in Arm A.	Drug: Cytarabine; Given IV; Other Names: CHX-3311 U-19920 ; Other: Laboratory Biomarker Analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Response Rate(CR/CRi) Rate [Up to 3 years]

   For descriptive purposes, the CR/CRi (complete response/Complete response with incomplete blood count recovery) rate will be reported at the end of the study separately for Arm A and Arm B. Responses are following definitions consistent with those published by Dohner H, Estey EH, Amadori S, et al. CR is defined as Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/μL and a platelet count of 100,000/μL, absence of blasts in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. CRi: All CR criteria except for residual neutropenia (ANC < 1000/μL)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adults with the established, pathologically confirmed diagnosis of relapsed AML

• AML that has relapsed at least once or is primary induction failure

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

• Patients must be able to give informed consent

• Female patients of childbearing age must have negative pregnancy test

• Serum creatinine =< 2.0 mg/dl

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 5 x upper limit normal (ULN), unless due to Gilbert's, hemolysis or leukemic infiltration

• Alkaline phosphatase =< 5 x ULN, unless due to Gilbert's, hemolysis or leukemic infiltration

• Bilirubin =< 2.0 mg/dl, unless due to Gilbert's, hemolysis or leukemic infiltration

• Left ventricular ejection fraction >= 45% by multi gated acquisition scan (MUGA) or echocardiogram

• Baseline Fridericia corrected QT (QTcF) < 480 msec

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 30 days after study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• Patients who have undergone stem cell transplantation (SCT), autologous or allogeneic, are eligible provided that they are >= 4 weeks from stem cell infusion, have no active graft-vs-host disease (GVHD), and meet other eligibility criteria

• Patients who fail primary induction therapy or relapse after achieving complete remission (CR) are eligible if they have undergone no more than 2 prior cytotoxic regimens (a regimen is described as a distinctive planned collection of agent[s] and/or modalities to be utilized together during a cycle or course of therapy; i.e., induction+consolidation with or without stem cell transplant [SCT]), >= 2 weeks off cytotoxic chemotherapy, and >= 2 weeks off radiation therapy; patients must be off biologic therapies including hematopoietic growth factors >= 2 weeks; if using hydroxyurea (HU), steroids, imatinib or other tyrosine kinase inhibitors (TKIs), interferon, or other non-cytotoxics for blast count control, patient must be off for

= 24 hours (hrs) before starting MK-8776

• Fluvoxamine and ciprofloxacin must be stopped 7 days prior to day 1 of therapy, and be excluded during administration of study therapy; if the subject is using any of the other drugs that are cytochrome P4501A2 (CYP1A2) or P-glycoprotein (PgP) inhibitors, substitution should be considered and administration of these drugs should be avoided on the days of administration of MK-8776; in addition, smoking should be avoided and cytochrome P450 3A4 (CYP3A4) substrates with a narrow therapeutic index should be avoided: alfentanil, astemizole, cisapride, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, terfenadine

Exclusion Criteria:

• Any previous treatment with MK-8776

• Considered refractory or treatment failure to most recent treatment regimen, unless primary refractory

• Concomitant chemotherapy, radiation therapy, or immunotherapy

• Hyperleukocytosis with >= 50,000 blasts/uL (if using HU, steroids, tyrosine kinase/src inhibitors (including fms-related tyrosine kinase 3 [FLT3] inhibitors), arsenic, interferon or leukapheresis for blast count control, patient must be off those agents for 24 hours prior to beginning ara-C +/- MK-8776)

• Acute progranulocytic leukemia (APL, M3)

• Active disseminated intravascular coagulation (DIC)

• Active central nervous system (CNS) leukemia

• Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible

• Presence of other life-threatening illness

• Patients with mental deficits and/or psychiatric history that preclude them from giving informed consent or from following protocol

• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with MK-8776

• History of Fridericia corrected QT (QTcF) prolongation greater than grade 1 or 480 msec

• Subjects with the following cardiac risk factors must be excluded: transmural myocardial infarction (MI) within prior 6 months, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack (TIA) or seizure disorder within 6 months prior to study drug administration

• Subjects with history of risk factors for torsades de pointes: clinical history of heart failure (New York Heart Association [NYHA] class III or IV), hypo- or hyper-kalemia or hypomagnesemia (supplementation to bring levels within normal limits prior to administration of MK-8776 is acceptable) or family history of Long QT Syndrome

• Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral therapy or who have a prior history of acquired immunodeficiency syndrome (AIDS) indicator conditions, other than history of lymphoma more than 3 years remote

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
2	Blood and Marrow Transplant Group of Georgia	Atlanta	Georgia	United States	30342
3	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital	Baltimore	Maryland	United States	21231
4	Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21287
5	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: B. Smith, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01870596
• Other Study ID Numbers: NCI-2013-01097; NCI-2013-01097; J1319; 9362; U01CA070095; P30CA006973
• First Posted: Jun 6, 2013
• Last Update Posted: Sep 1, 2016
• Last Verified: Jul 1, 2016

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Cytarabine

Study Results

Participant Flow

Arm/Group Title	Arm A (Cytarabine, Chk1 Inhibitor SCH 900776)	Arm B (Cytarabine)
Arm/Group Description	Patients receive cytarabine IV continuously over 72 hours on days 1-3 and 10-12 and Chk1 inhibitor SCH 900776 IV over 30 minutes on days 2, 3, 11, and 12. Cytarabine: Given IV CHK1 Inhibitor SCH 900776: Given IV Laboratory Biomarker Analysis: Correlative studies	Patients receive cytarabine as in Arm A. Cytarabine: Given IV Laboratory Biomarker Analysis: Correlative studies
Period Title: Overall Study
STARTED	14	18
COMPLETED	14	18
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm A (Cytarabine, Chk1 Inhibitor SCH 900776)	Arm B (Cytarabine)	Total
Arm/Group Description	Patients receive cytarabine IV continuously over 72 hours on days 1-3 and 10-12 and Chk1 inhibitor SCH 900776 IV over 30 minutes on days 2, 3, 11, and 12. Cytarabine: Given IV CHK1 Inhibitor SCH 900776: Given IV Laboratory Biomarker Analysis: Correlative studies	Patients receive cytarabine as in Arm A. Cytarabine: Given IV Laboratory Biomarker Analysis: Correlative studies	Total of all reporting groups
Overall Participants	14	18	32
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 78.6%	12 66.7%	23 71.9%
>=65 years	3 21.4%	6 33.3%	9 28.1%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60	60	60
Sex: Female, Male (Count of Participants)
Female	6 42.9%	9 50%	15 46.9%
Male	8 57.1%	9 50%	17 53.1%
Region of Enrollment (participants) [Number]
United States	14 100%	18 100%	32 100%

Outcome Measures

1. Primary Outcome

Title	Response Rate(CR/CRi) Rate
Description	For descriptive purposes, the CR/CRi (complete response/Complete response with incomplete blood count recovery) rate will be reported at the end of the study separately for Arm A and Arm B. Responses are following definitions consistent with those published by Dohner H, Estey EH, Amadori S, et al. CR is defined as Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/μL and a platelet count of 100,000/μL, absence of blasts in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. CRi: All CR criteria except for residual neutropenia (ANC < 1000/μL)
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A (Cytarabine, Chk1 Inhibitor SCH 900776)	Arm B (Cytarabine)
Arm/Group Description	Patients receive cytarabine IV continuously over 72 hours on days 1-3 and 10-12 and Chk1 inhibitor SCH 900776 IV over 30 minutes on days 2, 3, 11, and 12. Cytarabine: Given IV CHK1 Inhibitor SCH 900776: Given IV Laboratory Biomarker Analysis: Correlative studies	Patients receive cytarabine as in Arm A. Cytarabine: Given IV Laboratory Biomarker Analysis: Correlative studies
Measure Participants	14	18
Number [participants]	6 42.9%	9 50%

Adverse Events

Arm/Group Title	Arm A (Cytarabine, Chk1 Inhibitor SCH 900776)		Arm B (Cytarabine)
Arm/Group Description	Patients receive cytarabine IV continuously over 72 hours on days 1-3 and 10-12 and Chk1 inhibitor SCH 900776 IV over 30 minutes on days 2, 3, 11, and 12. Cytarabine: Given IV CHK1 Inhibitor SCH 900776: Given IV Laboratory Biomarker Analysis: Correlative studies		Patients receive cytarabine as in Arm A. Cytarabine: Given IV Laboratory Biomarker Analysis: Correlative studies
All Cause Mortality
	Arm A (Cytarabine, Chk1 Inhibitor SCH 900776)		Arm B (Cytarabine)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A (Cytarabine, Chk1 Inhibitor SCH 900776)		Arm B (Cytarabine)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/14 (14.3%)		6/18 (33.3%)
Cardiac disorders
Cardiac arrhythmia	0/14 (0%)	0	2/18 (11.1%)	2
General disorders
death multi system organ failure	0/14 (0%)	0	1/18 (5.6%)	1
Infections and infestations
Sepsis	1/14 (7.1%)	1	2/18 (11.1%)	2
Renal and urinary disorders
Acute Kidney Injusry	1/14 (7.1%)	1	1/18 (5.6%)	1
Other (Not Including Serious) Adverse Events
	Arm A (Cytarabine, Chk1 Inhibitor SCH 900776)		Arm B (Cytarabine)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/14 (100%)		18/18 (100%)
Blood and lymphatic system disorders
Febrile Neutropenia	5/14 (35.7%)	5	7/18 (38.9%)	7
Hemolysis	0/14 (0%)	0	1/18 (5.6%)	1
Cardiac disorders
Atrial Fibrillation	1/14 (7.1%)	1	1/18 (5.6%)	1
Sinus Tachycardia	1/14 (7.1%)	1	0/18 (0%)	0
Gastrointestinal disorders
abdominal pain	1/14 (7.1%)	1	0/18 (0%)	0
Constipation	1/14 (7.1%)	1	1/18 (5.6%)	1
Colonic hemorrhage	0/14 (0%)	0	1/18 (5.6%)	1
diarrhea	1/14 (7.1%)	1	0/18 (0%)	0
Dyspepsia	1/14 (7.1%)	1	0/18 (0%)	0
Dry mouth	0/14 (0%)	0	1/18 (5.6%)	1
Gastroesophageal reflux disease	2/14 (14.3%)	2	2/18 (11.1%)	2
Hemorrhoids	0/14 (0%)	0	1/18 (5.6%)	1
Mucositis ora	5/14 (35.7%)	5	2/18 (11.1%)	2
Nausea	3/14 (21.4%)	3	2/18 (11.1%)	2
General disorders
edema limbs	0/14 (0%)	0	1/18 (5.6%)	1
Fatigue	3/14 (21.4%)	3	1/18 (5.6%)	1
fever	1/14 (7.1%)	1	2/18 (11.1%)	2
Infusion related reaction	2/14 (14.3%)	2	1/18 (5.6%)	1
Infections and infestations
Lung infection	0/14 (0%)	0	1/18 (5.6%)	1
Phlebitis infective	0/14 (0%)	0	1/18 (5.6%)	1
Sepsis	1/14 (7.1%)	1	1/18 (5.6%)	1
Sinusitis	0/14 (0%)	0	1/18 (5.6%)	1
Skin Infection	1/14 (7.1%)	1	0/18 (0%)	0
Tooth infection	1/14 (7.1%)	1	0/18 (0%)	0
Injury, poisoning and procedural complications
Aspartate aminotransferase increased	0/14 (0%)	0	2/18 (11.1%)	2
Bruising	0/14 (0%)	0	1/18 (5.6%)	1
Investigations
Alanine aminotransferase increased	1/14 (7.1%)	1	3/18 (16.7%)	3
ADVERSE_EVENTS 9362 9362-GA079-129 1 Investigations Alkaline phosphatase increased	1/14 (7.1%)	1	1/18 (5.6%)	1
Aspartate aminotransferase increased	1/14 (7.1%)	1	0/18 (0%)	0
Blood bilirubin increased	1/14 (7.1%)	1	0/18 (0%)	0
Creatinine increased	0/14 (0%)	0	1/18 (5.6%)	1
Electrocardiogram QT corrected interval prolonged	4/14 (28.6%)	4	0/18 (0%)	0
INR increased	1/14 (7.1%)	1	0/18 (0%)	0
Metabolism and nutrition disorders
anorexia	1/14 (7.1%)	1	0/18 (0%)	0
Hyperglycemia	4/14 (28.6%)	4	1/18 (5.6%)	1
Hypermagnesemia	1/14 (7.1%)	1	0/18 (0%)	0
Hypoalbuminemia	1/14 (7.1%)	1	0/18 (0%)	0
Hypocalcemia	1/14 (7.1%)	1	5/18 (27.8%)	5
Hypokalemia	0/14 (0%)	0	3/18 (16.7%)	3
Hyponatremia	1/14 (7.1%)	1	0/18 (0%)	0
Hypomagnesemia	0/14 (0%)	0	1/18 (5.6%)	1
Hypophosphatemia	0/14 (0%)	0	1/18 (5.6%)	1
Tumor Lysis Syndrome	0/14 (0%)	0	1/18 (5.6%)	1
Musculoskeletal and connective tissue disorders
back pain	1/14 (7.1%)	1	0/18 (0%)	0
Generalized muscle weakness	1/14 (7.1%)	1	1/18 (5.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/14 (7.1%)	1	0/18 (0%)	0
Nervous system disorders
Dysgeusia	0/14 (0%)	0	1/18 (5.6%)	1
Headache	0/14 (0%)	0	1/18 (5.6%)	1
Peripheral sensory neuropathy	1/14 (7.1%)	1	0/18 (0%)	0
Psychiatric disorders
delerium	1/14 (7.1%)	1	0/18 (0%)	0
Depression	0/14 (0%)	0	1/18 (5.6%)	1
Hallucinations	0/14 (0%)	0	1/18 (5.6%)	1
Renal and urinary disorders
acute kidney injury	0/14 (0%)	0	1/18 (5.6%)	1
Urinary Incontinence	0/14 (0%)	0	1/18 (5.6%)	1
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/14 (7.1%)	1	0/18 (0%)	0
cough	0/14 (0%)	0	1/18 (5.6%)	1
Epistaxis	0/14 (0%)	0	1/18 (5.6%)	1
Hypoxia	1/14 (7.1%)	1	0/18 (0%)	0
Postnasal drip	0/14 (0%)	0	1/18 (5.6%)	1
Respiratory Failure	0/14 (0%)	0	1/18 (5.6%)	1
Skin and subcutaneous tissue disorders
alopecia	1/14 (7.1%)	1	0/18 (0%)	0
Erythroderma	1/14 (7.1%)	1	0/18 (0%)	0
Palmar-plantar erythrodysesthesia syndrome	3/14 (21.4%)	3	1/18 (5.6%)	1
Rash maculo-papular	3/14 (21.4%)	3	3/18 (16.7%)	3
Vascular disorders
Hypertension	3/14 (21.4%)	3	1/18 (5.6%)	1
Hypotension	1/14 (7.1%)	1	0/18 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.