Trial Outcomes & Findings for Dose Escalation Phase I/II Study of Lovastatin With High-Dose Cytarabine for Refractory or Relapsed AML (NCT NCT00583102)
NCT ID: NCT00583102
Last Updated: 2018-01-05
Results Overview
The primary study end point will be complete remission rate. Complete Remission (CR): Complete remission is defined as the presence of all of the following: Peripheral Blood Counts (sustained \> 30 days) * Absolute neutrophil count ³1500/ml. * Platelet count ³100,000/ml. * No leukemic blasts in the peripheral blood. * Transfusion independent for red cells and platelets. Bone Marrow * Cellularity \>20% with maturation of all cell lines. * No Auer rods. * \<5% blast cells. No extramedullary leukemia (such as CNS or soft tissue involvement). OR Complete Response with Incomplete Platelet Recovery (CRp): CRp satisfies all CR criteria except platelets \< 100,000/µL. Partial Remission (PR): Must meet all criteria of a CR except that the bone marrow may contain 5-24% blasts. Treatment Failure: Failure to achieve a CR.
Recruitment status
TERMINATED
Study phase
PHASE1/PHASE2
Target enrollment
23 participants
Primary outcome timeframe
5 weeks
Results posted on
2018-01-05
Participant Flow
Participant milestones
| Measure |
Lovastatin Followed by Cytarabine
The subject will receive high dose cytarabine as well as lovastatin. The subject will take doses of lovastatin twice a day, about 12 hours apart. On the third day, the subject will begin high-dose cytarabine IV over 3 hours, twice a day, starting 1 hour after the lovastatin dose for 5 days.
Cytarabine: Cytarabine dosage: 3.0 g/m2 IV over 3 hours every 12 hours on days 3-7.
Lovastatin: Lovastatin dosage: The first dose level will be lovastatin at 0.5 mg/kg/day. After each patient reaches day 14 subsequent patients will be treated at incrementally increasing doses that are 1 mg/kg/day, 2 mg/kg/day, 4 mg/kg/day, 8 mg/kg/day, 12 mg/kg/day, 18 mg/kg/day, and 24 mg/kg/day. If MTD is not reached at this dose of 24 mg/kg/day further dose escalations will occur with a 33% increase in dose at each level rounded to the nearest mg/kg/day.
|
|---|---|
|
Overall Study
STARTED
|
23
|
|
Overall Study
COMPLETED
|
20
|
|
Overall Study
NOT COMPLETED
|
3
|
Reasons for withdrawal
| Measure |
Lovastatin Followed by Cytarabine
The subject will receive high dose cytarabine as well as lovastatin. The subject will take doses of lovastatin twice a day, about 12 hours apart. On the third day, the subject will begin high-dose cytarabine IV over 3 hours, twice a day, starting 1 hour after the lovastatin dose for 5 days.
Cytarabine: Cytarabine dosage: 3.0 g/m2 IV over 3 hours every 12 hours on days 3-7.
Lovastatin: Lovastatin dosage: The first dose level will be lovastatin at 0.5 mg/kg/day. After each patient reaches day 14 subsequent patients will be treated at incrementally increasing doses that are 1 mg/kg/day, 2 mg/kg/day, 4 mg/kg/day, 8 mg/kg/day, 12 mg/kg/day, 18 mg/kg/day, and 24 mg/kg/day. If MTD is not reached at this dose of 24 mg/kg/day further dose escalations will occur with a 33% increase in dose at each level rounded to the nearest mg/kg/day.
|
|---|---|
|
Overall Study
Adverse Event
|
3
|
Baseline Characteristics
Dose Escalation Phase I/II Study of Lovastatin With High-Dose Cytarabine for Refractory or Relapsed AML
Baseline characteristics by cohort
| Measure |
Lovastatin Followed by Cytarabine
n=23 Participants
The subject will receive high dose cytarabine as well as lovastatin. The subject will take doses of lovastatin twice a day, about 12 hours apart. On the third day, the subject will begin high-dose cytarabine IV over 3 hours, twice a day, starting 1 hour after the lovastatin dose for 5 days.
Cytarabine: Cytarabine dosage: 3.0 g/m2 IV over 3 hours every 12 hours on days 3-7.
Lovastatin: Lovastatin dosage: The first dose level will be lovastatin at 0.5 mg/kg/day. After each patient reaches day 14 subsequent patients will be treated at incrementally increasing doses that are 1 mg/kg/day, 2 mg/kg/day, 4 mg/kg/day, 8 mg/kg/day, 12 mg/kg/day, 18 mg/kg/day, and 24 mg/kg/day. If MTD is not reached at this dose of 24 mg/kg/day further dose escalations will occur with a 33% increase in dose at each level rounded to the nearest mg/kg/day.
|
|---|---|
|
Age, Categorical
<=18 years
|
0 Participants
n=5 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
12 Participants
n=5 Participants
|
|
Age, Categorical
>=65 years
|
11 Participants
n=5 Participants
|
|
Age, Continuous
|
64.3 years
n=5 Participants
|
|
Sex: Female, Male
Female
|
11 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
12 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
23 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 5 weeksPopulation: 7 patients out of the 20 who completed the trial were primary refractory AML, so as per protocol these patients were not included for assessment and the early stopping rule.
The primary study end point will be complete remission rate. Complete Remission (CR): Complete remission is defined as the presence of all of the following: Peripheral Blood Counts (sustained \> 30 days) * Absolute neutrophil count ³1500/ml. * Platelet count ³100,000/ml. * No leukemic blasts in the peripheral blood. * Transfusion independent for red cells and platelets. Bone Marrow * Cellularity \>20% with maturation of all cell lines. * No Auer rods. * \<5% blast cells. No extramedullary leukemia (such as CNS or soft tissue involvement). OR Complete Response with Incomplete Platelet Recovery (CRp): CRp satisfies all CR criteria except platelets \< 100,000/µL. Partial Remission (PR): Must meet all criteria of a CR except that the bone marrow may contain 5-24% blasts. Treatment Failure: Failure to achieve a CR.
Outcome measures
| Measure |
Lovastatin Followed by Cytarabine
n=13 Participants
The subject will receive high dose cytarabine as well as lovastatin. The subject will take doses of lovastatin twice a day, about 12 hours apart. On the third day, the subject will begin high-dose cytarabine IV over 3 hours, twice a day, starting 1 hour after the lovastatin dose for 5 days.
Cytarabine: Cytarabine dosage: 3.0 g/m2 IV over 3 hours every 12 hours on days 3-7.
Lovastatin: Lovastatin dosage: The first dose level will be lovastatin at 0.5 mg/kg/day. After each patient reaches day 14 subsequent patients will be treated at incrementally increasing doses that are 1 mg/kg/day, 2 mg/kg/day, 4 mg/kg/day, 8 mg/kg/day, 12 mg/kg/day, 18 mg/kg/day, and 24 mg/kg/day. If MTD is not reached at this dose of 24 mg/kg/day further dose escalations will occur with a 33% increase in dose at each level rounded to the nearest mg/kg/day.
|
|---|---|
|
Complete Remission Rate
Complete Remission(CR)
|
7 Participants
|
|
Complete Remission Rate
Partial Remission(PR)
|
3 Participants
|
|
Complete Remission Rate
Treatment Failure
|
3 Participants
|
Adverse Events
Lovastatin Followed by Cytarabine
Serious events: 10 serious events
Other events: 20 other events
Deaths: 6 deaths
Serious adverse events
| Measure |
Lovastatin Followed by Cytarabine
n=23 participants at risk
The subject will receive high dose cytarabine as well as lovastatin. The subject will take doses of lovastatin twice a day, about 12 hours apart. On the third day, the subject will begin high-dose cytarabine IV over 3 hours, twice a day, starting 1 hour after the lovastatin dose for 5 days.
Lovastatin and Cytarabine: Cytarabine dosage: 3.0 g/m2 IV over 3 hours every 12 hours on days 3-7.
Lovastatin dosage: The first dose level will be lovastatin at 0.5 mg/kg/day. After each patient reaches day 14 subsequent patients will be treated at incrementally increasing doses that are 1 mg/kg/day, 2 mg/kg/day, 4 mg/kg/day, 8 mg/kg/day, 12 mg/kg/day, 18 mg/kg/day, and 24 mg/kg/day. If MTD is not reached at this dose of 24 mg/kg/day further dose escalations will occur with a 33% increase in dose at each level rounded to the nearest mg/kg/day.
|
|---|---|
|
Cardiac disorders
Cardiac left ventricular function
|
4.3%
1/23 • Number of events 1
|
|
Cardiac disorders
Cardiac troponin T (cTnT)
|
4.3%
1/23 • Number of events 1
|
|
Blood and lymphatic system disorders
Fibrinogen
|
8.7%
2/23 • Number of events 2
|
|
Infections and infestations
Febrile neutropenia
|
4.3%
1/23 • Number of events 1
|
|
Metabolism and nutrition disorders
Hypokalemia,Hypophosphatemia,elevated ALT
|
4.3%
1/23 • Number of events 1
|
|
Metabolism and nutrition disorders
Hypoalbuminemia
|
4.3%
1/23 • Number of events 1
|
|
Hepatobiliary disorders
Elevated GGT
|
4.3%
1/23 • Number of events 3
|
|
Blood and lymphatic system disorders
Decreased WBCs, Grade 3 lymphopenia
|
4.3%
1/23 • Number of events 1
|
|
Blood and lymphatic system disorders
Thrombocytopenia
|
4.3%
1/23 • Number of events 1
|
|
Blood and lymphatic system disorders
Anemia
|
4.3%
1/23 • Number of events 1
|
|
Blood and lymphatic system disorders
Decreased albumin
|
4.3%
1/23 • Number of events 1
|
|
Respiratory, thoracic and mediastinal disorders
Pneumonia infection
|
4.3%
1/23 • Number of events 1
|
|
Gastrointestinal disorders
Cholecystitis
|
4.3%
1/23 • Number of events 1
|
|
Blood and lymphatic system disorders
Pancytopenia
|
8.7%
2/23 • Number of events 2
|
|
Cardiac disorders
Stroke
|
4.3%
1/23 • Number of events 1
|
|
General disorders
Anorexia
|
4.3%
1/23 • Number of events 1
|
|
Infections and infestations
Candidemia
|
4.3%
1/23 • Number of events 1
|
|
Cardiac disorders
Thrombosis/embolism
|
4.3%
1/23 • Number of events 1
|
Other adverse events
| Measure |
Lovastatin Followed by Cytarabine
n=23 participants at risk
The subject will receive high dose cytarabine as well as lovastatin. The subject will take doses of lovastatin twice a day, about 12 hours apart. On the third day, the subject will begin high-dose cytarabine IV over 3 hours, twice a day, starting 1 hour after the lovastatin dose for 5 days.
Lovastatin and Cytarabine: Cytarabine dosage: 3.0 g/m2 IV over 3 hours every 12 hours on days 3-7.
Lovastatin dosage: The first dose level will be lovastatin at 0.5 mg/kg/day. After each patient reaches day 14 subsequent patients will be treated at incrementally increasing doses that are 1 mg/kg/day, 2 mg/kg/day, 4 mg/kg/day, 8 mg/kg/day, 12 mg/kg/day, 18 mg/kg/day, and 24 mg/kg/day. If MTD is not reached at this dose of 24 mg/kg/day further dose escalations will occur with a 33% increase in dose at each level rounded to the nearest mg/kg/day.
|
|---|---|
|
Gastrointestinal disorders
Nausea
|
26.1%
6/23 • Number of events 10
|
|
Gastrointestinal disorders
Emesis
|
13.0%
3/23 • Number of events 3
|
|
Blood and lymphatic system disorders
Disseminated intravascular coagulation
|
4.3%
1/23 • Number of events 1
|
|
Respiratory, thoracic and mediastinal disorders
Nose bleed
|
8.7%
2/23 • Number of events 2
|
|
Infections and infestations
Febrile neutropenia
|
21.7%
5/23 • Number of events 5
|
|
General disorders
Fatigue
|
13.0%
3/23 • Number of events 4
|
|
Gastrointestinal disorders
Diarrhea
|
30.4%
7/23 • Number of events 8
|
|
Skin and subcutaneous tissue disorders
Rash
|
4.3%
1/23 • Number of events 2
|
|
Nervous system disorders
Thumb numbness
|
4.3%
1/23 • Number of events 1
|
|
Gastrointestinal disorders
Anorexia
|
8.7%
2/23 • Number of events 3
|
|
Gastrointestinal disorders
c-difficile infection
|
4.3%
1/23 • Number of events 1
|
|
Cardiac disorders
Tachycardia
|
4.3%
1/23 • Number of events 1
|
|
Gastrointestinal disorders
Abdominal pain
|
17.4%
4/23 • Number of events 4
|
|
Cardiac disorders
Edema
|
13.0%
3/23 • Number of events 3
|
|
Gastrointestinal disorders
GI bleed
|
4.3%
1/23 • Number of events 1
|
|
Respiratory, thoracic and mediastinal disorders
Shortness of breath
|
4.3%
1/23 • Number of events 1
|
|
Blood and lymphatic system disorders
Fluid overload
|
4.3%
1/23 • Number of events 1
|
|
Cardiac disorders
Hypertension
|
4.3%
1/23 • Number of events 2
|
|
Psychiatric disorders
Depression
|
4.3%
1/23 • Number of events 1
|
|
Hepatobiliary disorders
Bilirubin
|
13.0%
3/23 • Number of events 3
|
|
Metabolism and nutrition disorders
Hypocalcemia
|
17.4%
4/23 • Number of events 4
|
|
Metabolism and nutrition disorders
Hypophosphatemia
|
4.3%
1/23 • Number of events 1
|
|
Metabolism and nutrition disorders
Hypokalemia
|
26.1%
6/23 • Number of events 7
|
|
Gastrointestinal disorders
Enlarged gall bladder
|
4.3%
1/23 • Number of events 1
|
|
Respiratory, thoracic and mediastinal disorders
Pneumonia
|
4.3%
1/23 • Number of events 1
|
|
Gastrointestinal disorders
Dehydration
|
4.3%
1/23 • Number of events 1
|
|
Skin and subcutaneous tissue disorders
Urticaria
|
4.3%
1/23 • Number of events 1
|
|
General disorders
Weight gain
|
17.4%
4/23 • Number of events 4
|
|
Metabolism and nutrition disorders
Elevated Alkaline Phosphate
|
8.7%
2/23 • Number of events 2
|
|
Blood and lymphatic system disorders
Anemia
|
8.7%
2/23 • Number of events 2
|
|
Blood and lymphatic system disorders
Decreased white blood cell count
|
21.7%
5/23 • Number of events 6
|
|
Respiratory, thoracic and mediastinal disorders
Sore throat
|
8.7%
2/23 • Number of events 2
|
|
General disorders
Insomnia
|
4.3%
1/23 • Number of events 1
|
|
Injury, poisoning and procedural complications
Hemorrhage (Picc site)
|
4.3%
1/23 • Number of events 1
|
|
General disorders
Oral pain
|
8.7%
2/23 • Number of events 2
|
|
Nervous system disorders
Ataxia
|
4.3%
1/23 • Number of events 1
|
|
Metabolism and nutrition disorders
Hypoalbuminemia
|
26.1%
6/23 • Number of events 6
|
|
Metabolism and nutrition disorders
Elevated alanine transaminase (ALT)
|
17.4%
4/23 • Number of events 4
|
|
Metabolism and nutrition disorders
Elevated aspartate transaminase (AST)
|
17.4%
4/23 • Number of events 4
|
|
Metabolism and nutrition disorders
Elevated glucose
|
17.4%
4/23 • Number of events 4
|
|
Infections and infestations
Klebsiella oxytoca
|
4.3%
1/23 • Number of events 1
|
|
Metabolism and nutrition disorders
Decreased calcium
|
8.7%
2/23 • Number of events 2
|
|
Blood and lymphatic system disorders
Decreased hemoglobin
|
17.4%
4/23 • Number of events 4
|
|
Blood and lymphatic system disorders
Decreased platelets
|
17.4%
4/23 • Number of events 4
|
|
Blood and lymphatic system disorders
Increased Prothrombin time (PTT)
|
8.7%
2/23 • Number of events 3
|
|
Gastrointestinal disorders
Heartburn/dyspepsia
|
4.3%
1/23 • Number of events 1
|
|
Gastrointestinal disorders
Hemorrhoids
|
4.3%
1/23 • Number of events 1
|
|
Cardiac disorders
Chest pain
|
4.3%
1/23 • Number of events 1
|
|
Nervous system disorders
Syncope
|
4.3%
1/23 • Number of events 1
|
|
Blood and lymphatic system disorders
Edema
|
4.3%
1/23 • Number of events 1
|
|
Blood and lymphatic system disorders
Decreased lymphocytes
|
8.7%
2/23 • Number of events 2
|
|
Metabolism and nutrition disorders
Decreased sodium
|
4.3%
1/23 • Number of events 1
|
|
Metabolism and nutrition disorders
Decreased magnesium
|
4.3%
1/23 • Number of events 1
|
|
Renal and urinary disorders
Hematuria
|
4.3%
1/23 • Number of events 1
|
|
Metabolism and nutrition disorders
Hyperglycemia
|
8.7%
2/23 • Number of events 2
|
|
Cardiac disorders
Hypotension
|
4.3%
1/23 • Number of events 1
|
|
General disorders
Diaphoretic
|
4.3%
1/23 • Number of events 1
|
|
Endocrine disorders
Adrenal insufficiency
|
4.3%
1/23 • Number of events 1
|
|
General disorders
Oral lesion
|
4.3%
1/23 • Number of events 1
|
|
General disorders
Jaw/tooth pain
|
4.3%
1/23 • Number of events 1
|
|
Metabolism and nutrition disorders
Hyponatremia
|
13.0%
3/23 • Number of events 3
|
|
Metabolism and nutrition disorders
Hyperkalemia
|
4.3%
1/23 • Number of events 1
|
|
Metabolism and nutrition disorders
Decreased bicarbonate
|
13.0%
3/23 • Number of events 3
|
|
General disorders
Fever
|
4.3%
1/23 • Number of events 1
|
|
Gastrointestinal disorders
Constipation
|
13.0%
3/23 • Number of events 3
|
|
General disorders
White patch on tongue
|
4.3%
1/23 • Number of events 1
|
|
Infections and infestations
Oral infection, herpes simplex Type I
|
4.3%
1/23 • Number of events 1
|
|
Musculoskeletal and connective tissue disorders
T-spine nodule
|
4.3%
1/23 • Number of events 1
|
|
Vascular disorders
Deep Vein Thrombosis, upper extremity
|
4.3%
1/23 • Number of events 1
|
|
Gastrointestinal disorders
Difficulty swallowing
|
4.3%
1/23 • Number of events 1
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
8.7%
2/23 • Number of events 2
|
|
Infections and infestations
Toothache
|
8.7%
2/23 • Number of events 2
|
|
Infections and infestations
Infection, c-diff
|
4.3%
1/23 • Number of events 1
|
|
Injury, poisoning and procedural complications
Pain, bone marrow biopsy site
|
4.3%
1/23 • Number of events 1
|
|
Nervous system disorders
Neurological, poor finger-nose touch
|
4.3%
1/23 • Number of events 1
|
|
Musculoskeletal and connective tissue disorders
Pain, right thigh
|
4.3%
1/23 • Number of events 1
|
|
Skin and subcutaneous tissue disorders
Cellulitis, left hand
|
4.3%
1/23 • Number of events 1
|
|
Musculoskeletal and connective tissue disorders
Pain, right groin
|
4.3%
1/23 • Number of events 1
|
|
Psychiatric disorders
Mental status change
|
4.3%
1/23 • Number of events 2
|
|
Renal and urinary disorders
Pain, suprapubic
|
4.3%
1/23 • Number of events 1
|
|
Musculoskeletal and connective tissue disorders
Myalgia
|
8.7%
2/23 • Number of events 2
|
|
Psychiatric disorders
Anxiety
|
4.3%
1/23 • Number of events 1
|
|
General disorders
Neutropenia
|
4.3%
1/23 • Number of events 1
|
|
Blood and lymphatic system disorders
Lymphopenia
|
4.3%
1/23 • Number of events 1
|
|
Injury, poisoning and procedural complications
T-spine wound discomfort
|
4.3%
1/23 • Number of events 1
|
|
General disorders
Weight loss
|
13.0%
3/23 • Number of events 3
|
|
Infections and infestations
Oral thrush
|
8.7%
2/23 • Number of events 2
|
|
Metabolism and nutrition disorders
Increased GGT
|
8.7%
2/23 • Number of events 2
|
|
Infections and infestations
Infection with neutropenia (e-coli)
|
4.3%
1/23 • Number of events 1
|
|
Gastrointestinal disorders
Vomiting
|
4.3%
1/23 • Number of events 1
|
|
Infections and infestations
Neutropenic fever
|
8.7%
2/23 • Number of events 3
|
|
Skin and subcutaneous tissue disorders
Alopecia
|
4.3%
1/23 • Number of events 1
|
|
Blood and lymphatic system disorders
Decreased leukocytes
|
8.7%
2/23 • Number of events 4
|
|
Blood and lymphatic system disorders
Decreased ANC
|
4.3%
1/23 • Number of events 1
|
|
Gastrointestinal disorders
Stomatitis
|
4.3%
1/23 • Number of events 1
|
|
Cardiac disorders
Increased troponin t
|
4.3%
1/23 • Number of events 1
|
|
Cardiac disorders
Cardiac ventricular function
|
4.3%
1/23 • Number of events 1
|
|
Cardiac disorders
Congestive heart failure
|
4.3%
1/23 • Number of events 1
|
|
General disorders
Headache
|
4.3%
1/23 • Number of events 2
|
|
Injury, poisoning and procedural complications
Pain at new hickman line site
|
4.3%
1/23 • Number of events 1
|
|
Gastrointestinal disorders
Mucositis
|
4.3%
1/23 • Number of events 2
|
|
Blood and lymphatic system disorders
Neutrophils
|
4.3%
1/23 • Number of events 2
|
|
Infections and infestations
Abscessed tooth, infection
|
4.3%
1/23 • Number of events 1
|
|
Skin and subcutaneous tissue disorders
Thrombocytropenia
|
4.3%
1/23 • Number of events 1
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
4.3%
1/23 • Number of events 1
|
|
Gastrointestinal disorders
Diverticulitis
|
4.3%
1/23 • Number of events 1
|
|
Metabolism and nutrition disorders
Hyperphosphatemia
|
4.3%
1/23 • Number of events 1
|
|
Metabolism and nutrition disorders
Increased creatinine
|
4.3%
1/23 • Number of events 2
|
|
Respiratory, thoracic and mediastinal disorders
Hiccups
|
4.3%
1/23 • Number of events 1
|
|
Eye disorders
Visual disturbance
|
4.3%
1/23 • Number of events 1
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place