Trial Outcomes & Findings for Use of Ribavirin and Low Dose Ara-C to Treat Acute Myeloid Leukemia (NCT NCT01056523)
NCT ID: NCT01056523
Last Updated: 2023-10-02
Results Overview
This 3+3 designed aimed to determine recommended phase II dose (RP2D) based on pharmacokinetics (PK) and maximum tolerated dose (MTD). For the dose to be selected, a target steady state level of ribavirin 20 uM was needed for all patients and no more than 1 of 6 patients could have had dose limiting toxicity at that dose.
COMPLETED
PHASE1/PHASE2
29 participants
56 days
2023-10-02
Participant Flow
Patients were enrolled in this dose escalation study according to a 3+3 design. Patients not completing 28 days of therapy were replaced as they were not evaluable for the pharmacokinetic endpoint of steady state level of ribavirin.
Participant milestones
| Measure |
Dose Level 1
Ribavirin 1000 mg po bid x 28 days, cytarabine arabinoside 20 mg sc bid days 1 to 10
|
Dose Level 2
Ribavirin 1400 mg po bid x 28 days, cytarabine arabinoside 20 mg sc bid days 1 to 10
|
Dose Level 3
Ribavirin 1800 mg po bid x 28 days, cytarabine arabinoside 20 mg sc bid days 1 to 10
|
Dose Level 4
Ribavirin 2200 mg po bid x 28 days, cytarabine arabinoside 20 mg sc bid days 1 to 10
|
Dose Level 5
Ribavirin 1000 mg po bid x 28 days, cytarabine arabinoside 10 mg sc bid days 1 to 10
|
Dose Level 6
Ribavirin 1400 mg po bid x 28 days, cytarabine arabinoside 10 mg sc bid days 1 to 10
|
Dose Level 7
Ribavirin 1800 mg po bid x 28 days, cytarabine arabinoside 10 mg sc bid days 1 to 10
|
|---|---|---|---|---|---|---|---|
|
Overall Study
STARTED
|
4
|
3
|
5
|
6
|
3
|
3
|
5
|
|
Overall Study
COMPLETED
|
3
|
3
|
3
|
3
|
3
|
3
|
4
|
|
Overall Study
NOT COMPLETED
|
1
|
0
|
2
|
3
|
0
|
0
|
1
|
Reasons for withdrawal
| Measure |
Dose Level 1
Ribavirin 1000 mg po bid x 28 days, cytarabine arabinoside 20 mg sc bid days 1 to 10
|
Dose Level 2
Ribavirin 1400 mg po bid x 28 days, cytarabine arabinoside 20 mg sc bid days 1 to 10
|
Dose Level 3
Ribavirin 1800 mg po bid x 28 days, cytarabine arabinoside 20 mg sc bid days 1 to 10
|
Dose Level 4
Ribavirin 2200 mg po bid x 28 days, cytarabine arabinoside 20 mg sc bid days 1 to 10
|
Dose Level 5
Ribavirin 1000 mg po bid x 28 days, cytarabine arabinoside 10 mg sc bid days 1 to 10
|
Dose Level 6
Ribavirin 1400 mg po bid x 28 days, cytarabine arabinoside 10 mg sc bid days 1 to 10
|
Dose Level 7
Ribavirin 1800 mg po bid x 28 days, cytarabine arabinoside 10 mg sc bid days 1 to 10
|
|---|---|---|---|---|---|---|---|
|
Overall Study
Death
|
1
|
0
|
2
|
3
|
0
|
0
|
1
|
Baseline Characteristics
Use of Ribavirin and Low Dose Ara-C to Treat Acute Myeloid Leukemia
Baseline characteristics by cohort
| Measure |
Ribavirin and Cytarabine
n=29 Participants
Dose level 1 = 1000 mg po BID/ Dose level 2 = 1400 mg po BID/ Dose level 3 = 1800 mg po BID Drug: Cytarabine arabinoside Previous cohorts at 20 mg bid days 1 to 10 of every 28 day cycle. Dosage modified to 10 mg bid days 1 to 10 of every 28 day cycle for more recent cohorts.
|
|---|---|
|
Age, Continuous
|
65 years
n=93 Participants
|
|
Sex: Female, Male
Female
|
14 Participants
n=93 Participants
|
|
Sex: Female, Male
Male
|
15 Participants
n=93 Participants
|
|
FAB subtype
FAB sutype M4/M5
|
22 Participants
n=93 Participants
|
|
FAB subtype
Other FAB subtypes
|
7 Participants
n=93 Participants
|
PRIMARY outcome
Timeframe: 56 daysThis 3+3 designed aimed to determine recommended phase II dose (RP2D) based on pharmacokinetics (PK) and maximum tolerated dose (MTD). For the dose to be selected, a target steady state level of ribavirin 20 uM was needed for all patients and no more than 1 of 6 patients could have had dose limiting toxicity at that dose.
Outcome measures
| Measure |
Ribavirin-Cytarabine
n=29 Participants
Ribavirin: Dose level 1 = 1000 mg po BID/ Dose level 2 = 1400 mg po BID/ Dose level 3 = 1800 mg po BID
Cytarabine arabinoside: Previous cohorts at 20 mg bid days 1 to 10 of every 28 day cycle.
Dosage modified to 10 mg bid days 1 to 10 of every 28 day cycle for more recent cohorts.
|
|---|---|
|
Recommended Phase II Dose (RP2D) of Ribavirin When Given in Combination With Low-dose Ara-C
Ribavirin po bid for 28 days
|
1400 mg
|
|
Recommended Phase II Dose (RP2D) of Ribavirin When Given in Combination With Low-dose Ara-C
cytarabine arabinoside sc bid for 10 days
|
10 mg
|
SECONDARY outcome
Timeframe: 2-3 yearsPopulation: Only patients treated for 28 days or more were evaluable for response.
Overall response rate comprises complete response (\<5% blasts in the bone marrow, and in the peripheral blood Hgb more than or equal to 100 g/L, platelets more than or equal to 100x10-9/L, and neutrophils more than or equal to 1x10-9/L), partial response (5 to 25% blasts in the bone marrow and same peripheral blood parameters) and blast response (a greater than 50% decrease in bone marrow blast count and 2 log reduction in peripheral blood blast count, sustained for at least 28 days).
Outcome measures
| Measure |
Ribavirin-Cytarabine
n=21 Participants
Ribavirin: Dose level 1 = 1000 mg po BID/ Dose level 2 = 1400 mg po BID/ Dose level 3 = 1800 mg po BID
Cytarabine arabinoside: Previous cohorts at 20 mg bid days 1 to 10 of every 28 day cycle.
Dosage modified to 10 mg bid days 1 to 10 of every 28 day cycle for more recent cohorts.
|
|---|---|
|
Overall Response Rate
|
5 Participants
|
SECONDARY outcome
Timeframe: 2-3 yearsPopulation: Only patients treated for at least 28 days were evaluable for response.
Defined as \<5% blasts in the bone marrow and a hgb 100 g/L, platelets 100,000/uL, neutrophils 1000/uL.
Outcome measures
| Measure |
Ribavirin-Cytarabine
n=21 Participants
Ribavirin: Dose level 1 = 1000 mg po BID/ Dose level 2 = 1400 mg po BID/ Dose level 3 = 1800 mg po BID
Cytarabine arabinoside: Previous cohorts at 20 mg bid days 1 to 10 of every 28 day cycle.
Dosage modified to 10 mg bid days 1 to 10 of every 28 day cycle for more recent cohorts.
|
|---|---|
|
Complete Response Rate
|
2 Participants
|
SECONDARY outcome
Timeframe: 2-3 yearsPopulation: Only patients treated for 28 days or more were assessed for response.
Partial response was defined as 5 to 25% blasts in the bone marrow and Hgb \>100g/L, platelets \>100,000/ul and neutrophils \>1000/ul.
Outcome measures
| Measure |
Ribavirin-Cytarabine
n=21 Participants
Ribavirin: Dose level 1 = 1000 mg po BID/ Dose level 2 = 1400 mg po BID/ Dose level 3 = 1800 mg po BID
Cytarabine arabinoside: Previous cohorts at 20 mg bid days 1 to 10 of every 28 day cycle.
Dosage modified to 10 mg bid days 1 to 10 of every 28 day cycle for more recent cohorts.
|
|---|---|
|
Partial Response
|
1 Participants
|
SECONDARY outcome
Timeframe: 2-3 yearsPopulation: Only patients treated for 28 days or more were evaluable for response.
Blast response was defined as a greater than 50% decrease in bone marrow blast count and 2 log reduction in peripheral blood blast count, sustained for at least 28 days.
Outcome measures
| Measure |
Ribavirin-Cytarabine
n=21 Participants
Ribavirin: Dose level 1 = 1000 mg po BID/ Dose level 2 = 1400 mg po BID/ Dose level 3 = 1800 mg po BID
Cytarabine arabinoside: Previous cohorts at 20 mg bid days 1 to 10 of every 28 day cycle.
Dosage modified to 10 mg bid days 1 to 10 of every 28 day cycle for more recent cohorts.
|
|---|---|
|
Blast Response
|
2 Participants
|
Adverse Events
Ribavirin-Cytarabine
Serious adverse events
| Measure |
Ribavirin-Cytarabine
n=29 participants at risk
Ribavirin: Dose level 1 = 1000 mg po BID/ Dose level 2 = 1400 mg po BID/ Dose level 3 = 1800 mg po BID
Cytarabine arabinoside: Previous cohorts at 20 mg bid days 1 to 10 of every 28 day cycle.
Dosage modified to 10 mg bid days 1 to 10 of every 28 day cycle for more recent cohorts.
|
|---|---|
|
Nervous system disorders
Syncope
|
3.4%
1/29 • 44 months
|
|
Musculoskeletal and connective tissue disorders
Exacerbation of bone pain
|
3.4%
1/29 • 44 months
|
|
Nervous system disorders
Cerebrovascular hemorrhage
|
3.4%
1/29 • 44 months
|
|
Eye disorders
retinal hemorrhage
|
3.4%
1/29 • 44 months
|
|
Infections and infestations
visceral shingles
|
3.4%
1/29 • 44 months
|
|
Gastrointestinal disorders
Lower gastro-intestinal hemorrhage
|
3.4%
1/29 • 44 months
|
|
Infections and infestations
Sepsis
|
3.4%
1/29 • 44 months
|
Other adverse events
| Measure |
Ribavirin-Cytarabine
n=29 participants at risk
Ribavirin: Dose level 1 = 1000 mg po BID/ Dose level 2 = 1400 mg po BID/ Dose level 3 = 1800 mg po BID
Cytarabine arabinoside: Previous cohorts at 20 mg bid days 1 to 10 of every 28 day cycle.
Dosage modified to 10 mg bid days 1 to 10 of every 28 day cycle for more recent cohorts.
|
|---|---|
|
Blood and lymphatic system disorders
Hemolytic Anemia
|
13.8%
4/29 • 44 months
|
|
Gastrointestinal disorders
anorexia
|
10.3%
3/29 • 44 months
|
|
Gastrointestinal disorders
nausea
|
24.1%
7/29 • 44 months
|
|
Gastrointestinal disorders
diarrhea
|
17.2%
5/29 • 44 months
|
|
Gastrointestinal disorders
mucositis
|
41.4%
12/29 • 44 months
|
|
Gastrointestinal disorders
vomiting
|
20.7%
6/29 • 44 months
|
|
Gastrointestinal disorders
dry mouth
|
6.9%
2/29 • 44 months
|
|
Metabolism and nutrition disorders
low potassium
|
13.8%
4/29 • 44 months
|
|
Investigations
high ALT
|
13.8%
4/29 • 44 months
|
|
Blood and lymphatic system disorders
anemia
|
51.7%
15/29 • 44 months
|
|
Blood and lymphatic system disorders
neutropenia
|
17.2%
5/29 • 44 months
|
|
Blood and lymphatic system disorders
thrombocytopenia
|
24.1%
7/29 • 44 months
|
|
General disorders
fatigue
|
41.4%
12/29 • 44 months
|
|
General disorders
fever
|
20.7%
6/29 • 44 months
|
|
Investigations
high bilirubin
|
6.9%
2/29 • 44 months
|
|
General disorders
chills
|
6.9%
2/29 • 44 months
|
|
Investigations
high uric acid
|
6.9%
2/29 • 44 months
|
|
Nervous system disorders
dizziness
|
6.9%
2/29 • 44 months
|
|
Infections and infestations
infection
|
27.6%
8/29 • 44 months
|
|
Blood and lymphatic system disorders
febrile neutropenia
|
44.8%
13/29 • 44 months
|
|
Infections and infestations
pneumonia
|
10.3%
3/29 • 44 months
|
|
Musculoskeletal and connective tissue disorders
musculoskeletal pain
|
20.7%
6/29 • 44 months
|
|
Nervous system disorders
headache
|
6.9%
2/29 • 44 months
|
|
Respiratory, thoracic and mediastinal disorders
pleuritic pain
|
6.9%
2/29 • 44 months
|
|
Musculoskeletal and connective tissue disorders
generalized weakness
|
17.2%
5/29 • 44 months
|
|
Musculoskeletal and connective tissue disorders
muscle cramps
|
6.9%
2/29 • 44 months
|
|
Respiratory, thoracic and mediastinal disorders
dyspnea
|
20.7%
6/29 • 44 months
|
|
Respiratory, thoracic and mediastinal disorders
cough
|
10.3%
3/29 • 44 months
|
|
Skin and subcutaneous tissue disorders
rash
|
6.9%
2/29 • 44 months
|
|
Vascular disorders
hematoma
|
6.9%
2/29 • 44 months
|
|
Blood and lymphatic system disorders
petechia
|
17.2%
5/29 • 44 months
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place