Trial Outcomes & Findings for PKC412 and 5-Azacytidine (NCT NCT01202877)

NCT ID: NCT01202877

Last Updated: 2018-10-16

Results Overview

Criteria for response per international working group for Myelodysplastic Syndrome (MDS) \& acute myeloid leukemia (AML) where responders obtained a complete remission (CR), a CR with incomplete bone marrow recovery (CRi), a morphologic leukemia-free status (MLFS), or a partial remission (PR). CR: \<5% bone marrow blasts, neutrophil count\>1.0 X10⁹/L, \& platelet count\>100 X10⁹/L. CRi: all CR criteria except residual neutropenia (\<1.0 X10⁹/L) or thrombocytopenia (\<100 X10⁹/L). MLFS: \<5% blasts in bone marrow regardless of neutrophil \& platelet count in peripheral blood. PR: all CR criteria, except reduction\> 50% in bone marrow blasts, but still \>5%. Clinical responses evaluated using RECIST version 1.1 criteria after every two cycles, with confirmation of clinical response at 4 weeks after achieving response.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

54 participants

Primary outcome timeframe

6 months

Results posted on

2018-10-16

Participant Flow

Recruitment period: March 2, 2011 to October 01, 2013. All recruitment done at The University of Texas MD Anderson Cancer Center.

There were 57 participants for enrollment, one participant was a screen failure and two withdrew consent without receiving the study drug treatment and are therefore excluded from the study.

Participant milestones

Participant milestones
Measure	Phase I: 5-azacytidine + PKC412 25 mg 5-azacytidine 75 mg/m2/day subcutaneously (SQ) or by vein (IV) on days 1-7 of a 28 day cycle. PKC412 25 mg orally twice daily for 14 days (days 8-21), of every 28 day cycle. Starting with cycle 2, PKC412 administered continuously (daily).	Phase I: 5-azacytidine + PKC412 50 mg 5-azacytidine 75 mg/m2/day subcutaneously (SQ) or by vein (IV) on days 1-7 of a 28 day cycle. PKC412 50 mg orally twice daily for 14 days (days 8-21), of every 28 day cycle. Starting with cycle 2, PKC412 administered continuously (daily).	Phase II: 5-azacytidine + PKC412 AZA 75 mg/m\^2 on days 1-7 and Midostaurin 50 mg bid orally on day 8-21 during the first cycle and continuously thereafter.
Overall Study STARTED	6	8	40
Overall Study COMPLETED	6	7	34
Overall Study NOT COMPLETED	0	1	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase I: 5-azacytidine + PKC412 50 mg 5-azacytidine 75 mg/m2/day subcutaneously (SQ) or by vein (IV) on days 1-7 of a 28 day cycle. PKC412 50 mg orally twice daily for 14 days (days 8-21), of every 28 day cycle. Starting with cycle 2, PKC412 administered continuously (daily).	Phase II: 5-azacytidine + PKC412 AZA 75 mg/m\^2 on days 1-7 and Midostaurin 50 mg bid orally on day 8-21 during the first cycle and continuously thereafter.
Overall Study Disease Progression	1	2
Overall Study Adverse Event	0	2
Overall Study Withdrawal by Subject	0	1
Overall Study Death	0	1

Baseline Characteristics

PKC412 and 5-Azacytidine

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I: 5-azacytidine + PKC412 25 mg n=6 Participants 5-azacytidine (AZA) 75 mg/m\^2/day subcutaneously (SQ) or by vein (IV) on days 1-7 of a 28 day cycle. PKC412 25 mg orally twice daily for 14 days (days 8-21), of every 28 day cycle. Starting with cycle 2, PKC412 administered continuously (daily).	Phase I: 5-azacytidine + PKC412 50 mg n=8 Participants AZA 75 mg/m\^2/day SQ or IV on days 1-7 of a 28 day cycle. PKC412 50 mg orally twice daily for 14 days (days 8-21), of every 28 day cycle. Starting with cycle 2, PKC412 administered continuously (daily).	Phase II: 5-azacytidine + PKC412 n=40 Participants AZA 75 mg/m\^2 on days 1-7 and Midostaurin 50 mg bid orally on day 8-21 during the first cycle and continuously thereafter.	Total n=54 Participants Total of all reporting groups
Age, Continuous	60 years n=5 Participants	62 years n=7 Participants	67 years n=5 Participants	65 years n=4 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	4 Participants n=7 Participants	16 Participants n=5 Participants	22 Participants n=4 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	4 Participants n=7 Participants	24 Participants n=5 Participants	32 Participants n=4 Participants
Region of Enrollment United States	6 Participants n=5 Participants	8 Participants n=7 Participants	40 Participants n=5 Participants	54 Participants n=4 Participants

PRIMARY outcome

Timeframe: 6 months

Outcome measures

Outcome measures
Measure	Phase I: 5-azacytidine + PKC412 25 mg n=6 Participants AZA 75 mg/m\^2/day subcutaneously (SQ) or by vein (IV) on days 1-7 of a 28 day cycle. PKC412 25 mg orally twice daily for 14 days (days 8-21), of every 28 day cycle. Starting with cycle 2, PKC412 administered continuously (daily).	Phase I: 5-azacytidine + PKC412 50 mg n=8 Participants AZA 75 mg/m\^2/day SQ or IV on days 1-7 of a 28 day cycle. PKC412 50 mg orally twice daily for 14 days (days 8-21), of every 28 day cycle. Starting with cycle 2, PKC412 administered continuously (daily).	Phase II: 5-azacytidine + PKC412 n=40 Participants AZA 75 mg/m\^2 on days 1-7 and PKC412 Midostaurin 50 mg bid orally on day 8-21 during the first cycle and continuously thereafter.
Participant Best Response Assessed Using Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 Complete w/Incomplete Bone Marrow Recovery (CRi)	1 participants	1 participants	4 participants
Participant Best Response Assessed Using Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 Complete Remission (CR)	0 participants	0 participants	1 participants
Participant Best Response Assessed Using Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 Morphologic Leukemia-Free Status (MLFS)	0 participants	0 participants	6 participants
Participant Best Response Assessed Using Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 Partial Remission (PR)	0 participants	0 participants	1 participants

PRIMARY outcome

Timeframe: 6 Months

Overall response defined as number of participants with response as follows: (OR = CR \[complete response (CR) rate\] + CRi \[complete remission with incomplete count recovery\] + PR \[partial remission\] + HI \[hematologic improvement\]) within 6 months of treatment initiation. complete remission (CR), a CR with incomplete bone marrow recovery (CRi), a morphologic leukemia-free status (MLFS), or a partial remission (PR). CR: \<5% bone marrow blasts, neutrophil count\>1.0 X10⁹/L, \& platelet count\>100 X10⁹/L. CRi: all CR criteria except residual neutropenia (\<1.0 X10⁹/L) or thrombocytopenia (\<100 X10⁹/L). MLFS: \<5% blasts in bone marrow regardless of neutrophil \& platelet count in peripheral blood. PR: all CR criteria, except reduction\> 50% in bone marrow blasts, but still \>5%.

Outcome measures

Outcome measures
Measure	Phase I: 5-azacytidine + PKC412 25 mg n=6 Participants AZA 75 mg/m\^2/day subcutaneously (SQ) or by vein (IV) on days 1-7 of a 28 day cycle. PKC412 25 mg orally twice daily for 14 days (days 8-21), of every 28 day cycle. Starting with cycle 2, PKC412 administered continuously (daily).	Phase I: 5-azacytidine + PKC412 50 mg n=8 Participants AZA 75 mg/m\^2/day SQ or IV on days 1-7 of a 28 day cycle. PKC412 50 mg orally twice daily for 14 days (days 8-21), of every 28 day cycle. Starting with cycle 2, PKC412 administered continuously (daily).	Phase II: 5-azacytidine + PKC412 n=40 Participants AZA 75 mg/m\^2 on days 1-7 and PKC412 Midostaurin 50 mg bid orally on day 8-21 during the first cycle and continuously thereafter.
Overall Response (OR) Within 6 Months	1 participants	1 participants	12 participants

Adverse Events

Phase I: 5-azacytidine + PKC412 25 mg

Serious events: 5 serious events

Other events: 6 other events

Deaths: 0 deaths

Phase I: 5-azacytidine + PKC412 50 mg

Serious events: 5 serious events

Other events: 8 other events

Deaths: 0 deaths

Phase II: 5-azacytidine + PKC412

Serious events: 29 serious events

Other events: 40 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Jorge Cortes, MD/Professor, Leukemia

The University of Texas (UT) MD Anderson Cancer Center

Phone: 1-877-632-6789

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Phase I: 5-azacytidine + PKC412 25 mg n=6 participants at risk AZA 75 mg/m\^2/day subcutaneously (SQ) or by vein (IV) on days 1-7 of a 28 day cycle. PKC412 25 mg orally twice daily for 14 days (days 8-21), of every 28 day cycle. Starting with cycle 2, PKC412 administered continuously (daily).	Phase I: 5-azacytidine + PKC412 50 mg n=8 participants at risk AZA 75 mg/m\^2/day SQ or IV on days 1-7 of a 28 day cycle. PKC412 50 mg orally twice daily for 14 days (days 8-21), of every 28 day cycle. Starting with cycle 2, PKC412 administered continuously (daily).	Phase II: 5-azacytidine + PKC412 n=40 participants at risk AZA 75 mg/m\^2 on days 1-7 and PKC412 Midostaurin 50 mg bid orally on day 8-21 during the first cycle and continuously thereafter.
Blood and lymphatic system disorders Anemia	100.0% 6/6 • Number of events 6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	100.0% 8/8 • Number of events 8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	100.0% 40/40 • Number of events 40 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Renal and urinary disorders Acute renal failure	0.00% 0/6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	12.5% 1/8 • Number of events 1 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	7.5% 3/40 • Number of events 3 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Blood and lymphatic system disorders Hemorrhage/Bleeding	0.00% 0/6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	0.00% 0/8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	20.0% 8/40 • Number of events 8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Gastrointestinal disorders Constipation	16.7% 1/6 • Number of events 1 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	12.5% 1/8 • Number of events 1 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	15.0% 6/40 • Number of events 6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
General disorders Fatigue	33.3% 2/6 • Number of events 2 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	12.5% 1/8 • Number of events 1 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	0.00% 0/40 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Investigations Hyperbilirubinemia	33.3% 2/6 • Number of events 2 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	0.00% 0/8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	17.5% 7/40 • Number of events 7 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Metabolism and nutrition disorders Hyperglycemia	0.00% 0/6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	0.00% 0/8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	7.5% 3/40 • Number of events 3 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Metabolism and nutrition disorders Hyperuricemia	0.00% 0/6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	0.00% 0/8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	5.0% 2/40 • Number of events 2 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Metabolism and nutrition disorders Hyperkalemia	16.7% 1/6 • Number of events 1 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	0.00% 0/8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	7.5% 3/40 • Number of events 3 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Metabolism and nutrition disorders Hypomagnesaemia	0.00% 0/6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	0.00% 0/8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	5.0% 2/40 • Number of events 2 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Metabolism and nutrition disorders Hyponatremia	16.7% 1/6 • Number of events 1 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	0.00% 0/8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	0.00% 0/40 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Infections and infestations Infections	66.7% 4/6 • Number of events 4 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	75.0% 6/8 • Number of events 6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	62.5% 25/40 • Number of events 25 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Gastrointestinal disorders Nausea/vomiting	50.0% 3/6 • Number of events 3 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	75.0% 6/8 • Number of events 6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	47.5% 19/40 • Number of events 19 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Blood and lymphatic system disorders Neutropenia	100.0% 6/6 • Number of events 6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	100.0% 8/8 • Number of events 8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	100.0% 40/40 • Number of events 40 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Investigations Electrocardiogram QTc prolongation	0.00% 0/6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	0.00% 0/8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	12.5% 5/40 • Number of events 5 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Skin and subcutaneous tissue disorders Skin rash	50.0% 3/6 • Number of events 3 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	62.5% 5/8 • Number of events 5 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	22.5% 9/40 • Number of events 9 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Cardiac disorders Tachycardia	16.7% 1/6 • Number of events 1 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	0.00% 0/8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	12.5% 5/40 • Number of events 5 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Hepatobiliary disorders Thrombosis	16.7% 1/6 • Number of events 1 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	12.5% 1/8 • Number of events 1 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	12.5% 5/40 • Number of events 5 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Renal and urinary disorders Abnormal liver function test (LFT)	0.00% 0/6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	0.00% 0/8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	15.0% 6/40 • Number of events 6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
General disorders Headache	16.7% 1/6 • Number of events 1 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	25.0% 2/8 • Number of events 2 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	12.5% 5/40 • Number of events 5 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Investigations Low Hemoglobin	100.0% 6/6 • Number of events 6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	100.0% 8/8 • Number of events 8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	100.0% 40/40 • Number of events 40 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Respiratory, thoracic and mediastinal disorders Mucositis	33.3% 2/6 • Number of events 2 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	25.0% 2/8 • Number of events 2 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	35.0% 14/40 • Number of events 14 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Investigations Platelet Increased	100.0% 6/6 • Number of events 6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	100.0% 8/8 • Number of events 8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	100.0% 40/40 • Number of events 40 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.
Investigations Prolongation of QT interval	0.00% 0/6 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	0.00% 0/8 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.	12.5% 5/40 • Number of events 5 • Adverse events captured from the time of the first protocol-specific intervention with each 21 day cycle until 30 days after the last dose of drug, about 6 months.