Phase I/II - Brentuximab/5-Azacytidine in Acute Myeloid Leukemia (AML)

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02096042
• Collaborator: Seagen Inc. (Industry)
• Enrollment: 1
• Location: 1
• Arms: 2
• Actual Duration (Months): 28
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This clinical research study is made up of 3 phases: a Pilot Phase, Phase 1, and Phase 2.

The goal of the Pilot Phase is to learn how safe it is to give the study drug brentuximab vedotin to patients with AML. The goal of Phase 1 is to learn more about the safety of the combination of brentuximab vedotin with azacytidine. The goal of Phase 2 is to learn if the combination of brentuximab vedotin and azacytidine can help to control AML.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Brentuximab Vedotin; Drug: 5-Azacytidine	Phase 1/Phase 2

Detailed Description

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. Up to 3 groups of 3-6 participants will be enrolled in the Pilot Phase, up to 3 groups of 3-6 participants will be enrolled in Phase I of the study, and up to 25 participants will be enrolled in Phase II.

If you are enrolled in the Pilot Phase, the dose of brentuximab vedotin you receive will depend on when you joined this study. The first group of participants will receive the highest dose level of brentuximab vedotin. If intolerable side effects are seen, up to 2 more groups will be enrolled and will receive a lower dose of brentuximab vedotin than the group before it. If intolerable side effects are not seen, the next phase of the study will begin.

If you are enrolled in Phase I, the dose of brentuximab vedotin you receive will depend on when you joined this study. The first group of participants will receive a lower dose level of brentuximab vedotin than the highest one that was tolerated in the Pilot Phase, and will also receive azacitidine. If intolerable side effects are seen, up to 2 more groups will be enrolled and will receive a lower dose of brentuximab vedotin than the group before it. If intolerable side effects are not seen, the next phase of the study will begin.

If you are enrolled in Phase 2, you will receive brentuximab vedotin at the highest dose that was tolerated in Phase 1.

All participants in Phases 1 and 2 will receive the same dose level of azacytidine.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive brentuximab vedotin by vein over 30 minutes on Days 1, 8, and 15 of each 28-day study cycle. If the disease appears to get better, or after cycle 4, the dose and schedule of brentuximab vedotin may be changed to monthly rather than weekly doses.

If you are in Phase 1 or Phase 2, you will also receive azacytidine by vein or as an injection under the skin on Days 1-7 of each cycle.

You may be given standard drugs to help decrease the risk of side effects. You may ask the study staff for information about how the drugs are given and their risks.

Study Visits:

On Day 1 of each cycle:

• You will have a physical exam.

• Blood (about 2-3 tablespoons) will be drawn for routine tests.

• You will have an EKG.

• Every 3 Cycles (Cycles 3, 6, 9, and so on), if you can become pregnant, blood (about 1 teaspoon) or urine will be collected for a pregnancy test.

On Days 8 and 22 of Cycle 1, blood (about 2-3 tablespoons) will be drawn for routine tests.

On Day 15 of Cycle 1:

• You will have a physical exam.

• Blood (about 2-3 tablespoons) will be drawn for routine tests.

On Day 28 of Cycle 1, then Day 1 of every 2 cycles after that (Cycles 3, 5, 7, and so on), you will have a bone marrow biopsy and/or aspirate to check the status of the disease. After any point that the disease appears to get better, this will be done every 3-4 cycles, or whenever your doctor thinks it is needed.

Length of Treatment:

You may receive the study drug for up to 12 cycles. You will no longer be able to receive the study drug(s) if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the end-of-study visit.

End-of-Study Visit:

About 28 days after your last dose of study drug, you will have an end-of-study visit:

• You will have a physical exam.

• Blood (about 2-3 tablespoons) will be drawn for routine tests.

• You will have an EKG to check your heart function.

• You may have a bone marrow biopsy and/or aspirate to check the status of the disease.

• If you can become pregnant, blood (about 1 teaspoon) or urine will be collected for a pregnancy test.

If the End-of-Study Visit occurs within 21 days of your last dose, you will be called by a member of the study team about 30-37 days after your last dose of study drug. You will be asked how you are feeling and about any side effects you may be having. This call will last about 5 minutes.

This is an investigational study. Brentuximab vedotin is FDA approved and commercially available for the treatment of certain types of lymphoma after previous treatments have failed. Its use in combination with azacitidine is investigational. Azacytidine is FDA approved and commercially available for the treatment of myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML).

The study doctor can explain how the study drug(s) are designed to work.

Up to 61 patients will take part in this study. All will be enrolled at MD Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of Weekly Schedule Of Brentuximab Vedotin Alone and In Combination With 5-Azacytidine In Cluster of Differentiation Antigen (CD30)-Positive Relapsed/Refractory Acute Myeloid Leukemia
• Actual Study Start Date: Apr 1, 2014
• Actual Primary Completion Date: Aug 1, 2016
• Actual Study Completion Date: Aug 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Brentuximab Vedotin Pilot Phase: Starting dose of Brentuximab Vedotin 1.2 mg/kg intravenous (IV) infusion over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle (+/- 3 days).	Drug: Brentuximab Vedotin; Pilot Phase: Starting dose of Brentuximab Vedotin 1.2 mg/kg intravenous (IV) infusion over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle. Phase I Dose-Escalation Phase: Starting dose of Brentuximab Vedotin 1.0 mg/kg IV (starting dose level 1), or one-dose level lower than the established MTD if the pilot portion of the study establishes a lower MTD, infusion over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle. Phase II Dose-Expansion Phase: Patients receive Brentuximab Vedotin at MTD from dose-escalation phase by vein on Days 1, 8, and 15 of each 28-day cycle.; Other Names: SGN-35 Adcetris
Experimental: Brentuximab Vedotin + 5-Azacytidine Phase I Dose-Escalation Phase: Starting dose of Brentuximab Vedotin 1.0 mg/kg IV (starting dose level 1), or one-dose level lower than the established MTD if the pilot portion of the study establishes a lower MTD, infusion over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle. All patients receive 5-azacytidine at 75 mg/m2/day by vein or subcutaneously on days 1-7 every 28 days. Phase II Dose-Expansion Phase: Patients receive Brentuximab Vedotin at MTD from dose-escalation phase by vein on Days 1, 8, and 15 of each 28-day cycle. Patients receive 5-Azacytidine at 75 mg/m2/day by vein or subcutaneously on days 1-7 every 28 days. Patients can receive up to a total of 12 cycles of treatment (weekly + monthly combined).	Drug: Brentuximab Vedotin; Pilot Phase: Starting dose of Brentuximab Vedotin 1.2 mg/kg intravenous (IV) infusion over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle. Phase I Dose-Escalation Phase: Starting dose of Brentuximab Vedotin 1.0 mg/kg IV (starting dose level 1), or one-dose level lower than the established MTD if the pilot portion of the study establishes a lower MTD, infusion over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle. Phase II Dose-Expansion Phase: Patients receive Brentuximab Vedotin at MTD from dose-escalation phase by vein on Days 1, 8, and 15 of each 28-day cycle.; Other Names: SGN-35 Adcetris ; Drug: 5-Azacytidine; Phase I Dose-Escalation Phase and Phase II Dose-Expansion Phase: 5-Azacytidine at 75 mg/m2/day by vein or subcutaneously on days 1-7 every 28 days.; Other Names: Azacytidine Azacitidine 5-aza Vidaza 5-AZC AZA-CR Ladakamycin NSC-102816

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of Brentuximab Vedotin in Combination With 5-Azacytidine [After 1, 28 day cycle]

   MTD defined as maximum dose at which <33% of patients experience a dose-limiting toxicity (DLT) during cycle 1.

2. Overall Response Rate [Response assessed after four 28-day cycles, up to 120 days]

   Response defined as number of participants with complete response (CR), CR with incomplete platelet recovery (CRp), CR with insufficient hematological recovery (CRi) or partial remission (PR).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Histologically or cytologically confirmed AML, other than acute promyelocytic leukemia, as defined by the 2008 World Health Organization (WHO) criteria that is relapsed or refractory to standard chemotherapy. Note: Newly-diagnosed AML patients who are 60 years or older and are not candidates for or have refused standard chemotherapy are also eligible for this trial.

2. AML blasts must express CD30 (>/=10% expression as assessed by flow-cytometry or 2+ expression by immunohistochemistry) (whenever possible CD30 expression will be assessed by both methods)

3. Age 18 years or older

4. Eastern Cooperative Oncology Group (ECOG) Performance Status score of </=3

5. The following baseline laboratory data: Serum bilirubin </=1.5 x upper limit of normal (ULN) or </= 3 x ULN for patients with Gilbert's disease; Serum creatinine </=1.5 x ULN AND creatinine clearance >30 ml/min; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) </=3 x ULN

6. Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (beta-hCG) pregnancy test result within 14 days prior to the first dose of brentuximab vedotin and must agree to use an effective contraception method during the study and for 30 days following the last dose of study drug. Females of non- childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy.

7. Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug

8. Patients or their legally authorized representative must provide written informed consent.

Exclusion Criteria:

1. History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years. Patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses).

2. Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association Class III-IV within 6 months prior to their first dose of brentuximab vedotin

3. Evidence of active cerebral/meningeal disease. Patients may have history of central nervous system (CNS) leukemic involvement if definitively treated with prior therapy and no evidence of active disease at the time of registration.

4. Previous treatment with any anti-CD30 directed therapy

5. Patients with previous allogeneic stem cell transplant (SCT) if they meet either of the following criteria: <100 days from allogeneic SCT, Acute or chronic graft-versus-host disease (GvHD), or Receiving immunosuppressive therapy as treatment for or prophylaxis against GvHD within the last 7 days

6. Patients with uncontrolled active infections (viral, bacterial, and fungal) are not eligible.

7. Known to be positive for hepatitis B by surface antigen expression

8. Known to have active hepatitis C infection (positive by polymerase chain reaction or on antiviral therapy for hepatitis C within the last 6 months)

9. Preexisting grade >/=2 peripheral neuropathy

10. Patients with uncontrolled diabetes mellitus

11. Current therapy with other systemic anti-neoplastic or anti-neoplastic investigational agents.

12. Chemotherapy (except hydroxyurea or emergent use of single-agent cytarabine for cytoreduction), radiotherapy, biologics, and/or other treatment with immunotherapy that is not completed 2 weeks prior to first dose of study drug, unless progressive disease is documented. NOTE: Hydroxyurea will be allowed during the first cycle of treatment

13. Females who are pregnant or lactating

14. Known hypersensitivity to any excipient contained in the drug formulation of brentuximab vedotin

15. History of progressive multifocal leukoencephalopathy (PML)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Seagen Inc.

Investigators

• Principal Investigator: Nitin Jain, MBBS, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT02096042
• Other Study ID Numbers: 2013-0706; NCI-2014-01114
• First Posted: Mar 26, 2014
• Last Update Posted: Sep 5, 2017
• Last Verified: Aug 1, 2017

• Keywords provided by M.D. Anderson Cancer Center: Leukemia; Acute Myeloid Leukemia; AML; CD30-Positive; Relapsed; Refractory; Brentuximab Vedotin; SGN-35; Adcetris; 5-Azacytidine; Azacytidine; Azacitidine; 5-aza; Vidaza; 5-AZC; AZA-CR; Ladakamycin; NSC-102816
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Azacitidine; Brentuximab Vedotin

Study Results

Participant Flow

Recruitment Details	Recruitment Period: April 24, 2014 to July 08, 2015. All recruitment done at The University of Texas MD Anderson Cancer Center.
Pre-assignment Detail	Study was terminated early due to low enrollment.

Arm/Group Title	Brentuximab Vedotin	Brentuximab Vedotin + 5-Azacytidine	MTD Brentuximab Vedotin + 5-Azacytidine
Arm/Group Description	Pilot Phase: Starting dose of Brentuximab Vedotin 1.2 mg/kg intravenous (IV) infusion over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle (+/- 3 days).	Phase I Dose-Escalation Phase: Starting dose of Brentuximab Vedotin 1.0 mg/kg IV (starting dose level 1), or one-dose level lower than the established MTD if the pilot portion of the study establishes a lower MTD, infusion over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle. 5-azacytidine at 75 mg/m2/day IV or subcutaneously on days 1-7 every 28 days.	Phase II Dose-Expansion Phase: Brentuximab Vedotin at MTD from dose-escalation phase IV on Days 1, 8, and 15 of each 28-day cycle. 5-Azacytidine at 75 mg/m2/day IV or subcutaneously on days 1-7 every 28 days.Up to 12 cycles of treatment (weekly + monthly combined).
Period Title: Overall Study
STARTED	1	0	0
COMPLETED	0	0	0
NOT COMPLETED	1	0	0

Baseline Characteristics

Arm/Group Title	Brentuximab Vedotin
Arm/Group Description	Pilot Phase: Starting dose of Brentuximab Vedotin 1.2 mg/kg intravenous (IV) infusion over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle (+/- 3 days).
Overall Participants	1
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	1 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	1 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Brentuximab Vedotin in Combination With 5-Azacytidine
Description	MTD defined as maximum dose at which <33% of patients experience a dose-limiting toxicity (DLT) during cycle 1.
Time Frame	After 1, 28 day cycle

Outcome Measure Data

Analysis Population Description

Study terminated early.

Arm/Group Title	Brentuximab Vedotin + 5-Azacytidine
Arm/Group Description	Phase I Dose-Escalation Phase: Starting dose of Brentuximab Vedotin 1.0 mg/kg IV (starting dose level 1), or one-dose level lower than the established MTD if the pilot portion of the study establishes a lower MTD, infusion over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle. 5-azacytidine at 75 mg/m2/day IV or subcutaneously on days 1-7 every 28 days.
Measure Participants	0

2. Primary Outcome

Title	Overall Response Rate
Description	Response defined as number of participants with complete response (CR), CR with incomplete platelet recovery (CRp), CR with insufficient hematological recovery (CRi) or partial remission (PR).
Time Frame	Response assessed after four 28-day cycles, up to 120 days

Outcome Measure Data

Analysis Population Description

Study was stopped with only one participant; no analysis done on outcome.

Arm/Group Title	Brentuximab Vedotin	Brentuximab Vedotin + 5-Azacytidine	MTD Brentuximab Vedotin + 5-Azacytidine
Arm/Group Description	Pilot Phase: Starting dose of Brentuximab Vedotin 1.2 mg/kg intravenous (IV) infusion over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle (+/- 3 days).	Phase I Dose-Escalation Phase: Starting dose of Brentuximab Vedotin 1.0 mg/kg IV (starting dose level 1), or one-dose level lower than the established MTD if the pilot portion of the study establishes a lower MTD, infusion over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle. 5-azacytidine at 75 mg/m2/day IV or subcutaneously on days 1-7 every 28 days.	Phase II Dose-Expansion Phase: Brentuximab Vedotin at MTD from dose-escalation phase IV on Days 1, 8, and 15 of each 28-day cycle. 5-Azacytidine at 75 mg/m2/day IV or subcutaneously on days 1-7 every 28 days.Up to 12 cycles of treatment (weekly + monthly combined).
Measure Participants	0	0	0

Adverse Events

Time Frame	Adverse event collection for first 28-day cycle.
Arm/Group Title	Brentuximab Vedotin
Arm/Group Description	Pilot Phase: Starting dose of Brentuximab Vedotin 1.2 mg/kg intravenous (IV) infusion over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle (+/- 3 days).
All Cause Mortality
	Brentuximab Vedotin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Brentuximab Vedotin
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Other (Not Including Serious) Adverse Events
	Brentuximab Vedotin
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Infections and infestations
Urinary Tract Infection	1/1 (100%)	1
Sepsis	1/1 (100%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/1 (100%)	1
Pain - extremity	1/1 (100%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/1 (100%)	1
Skin and subcutaneous tissue disorders
Erythema Multiforme	1/1 (100%)	1

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.