Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy

• Sponsor: Memorial Sloan Kettering Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01404949
• Collaborator: Northwestern University (Other), New York Presbyterian Hospital (Other), University of Southern California (Other), Princess Margaret Hospital, Canada (Other), National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 17
• Locations: 12
• Arm: 1
• Duration (Months): 115.1
• Patients Per Site: 1.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to find what effects, good and/or bad, treatment with two drugs has on leukemia. The first medicine is tretinoin (also called all-trans retinoic acid, ATRA, or Vesanoid). It is an approved medicine that causes the leukemia cells in APL to mature. It is related to vitamin A. The second is arsenic trioxide (Trisenox). It is an approved medicine for APL that comes back after earlier treatment.

APL is most often treated with tretinoin and standard chemotherapy drugs. These chemotherapy drugs can cause infection and bleeding. They can also damage the heart and normal bone marrow cells. This can lead to a second leukemia years later.

In this study, the investigators are using tretinoin and arsenic trioxide together. Both drugs work to treat APL. They have been used together in only a limited number of people. The investigators want to use these drugs together to reduce the amount of standard chemotherapy and decrease side effects. The patient will receive standard chemotherapy with a drug called idarubicin only if they have a higher chance of the leukemia coming back or a higher risk of side effects.

Condition or Disease	Intervention/Treatment	Phase
Acute Promyelocytic Leukemia	Drug: Tretinoin and Arsenic Trioxide	Phase 2

Detailed Description

Induction will consist of tretinoin 45 mg/m2 po daily (rounded up to the nearest 10mg) in two divided doses (25 mg/m2 in patients <20 years of age) for 35 days and ATO 0.15 mg/kg IV daily for 35 doses given 5-7 days per week. The drugs will then be discontinued, and the patient will be followed until a clinical complete remission is achieved. Idarubicin 12 mg/m2 IV for 4 doses will be added during induction on day 2 if the presenting WBC is >10,000/μl, or if the WBC increases to 5,000/μl on day 5, 10,000/μl on day 10, or 15,000/μl on day 15, because of the increased risk of the APL differentiation syndrome and relapse in these patients. Dexamethasone 10 mg twice daily with be given on days 1-14 of induction as prophylaxis for the APL differentiation syndrome. All patients will then receive four courses of consolidation with tretinoin 45 mg/m2 po daily (rounded up to the nearest 10mg) (25 mg/m2 in patients <20 years of age) for 15 days and ATO 0.15 mg/kg IV for 25 doses.

Patients with high-risk disease or who received Idarubicin during Induction may receive intrathecal cytarabine as CNS prophylaxis given by the treating physician during consolidation, at the discretion of the site PI. High-risk patients will also receive maintenance therapy with additional courses of tretinoin and ATO every 3 months for 2 years. Each maintenance course will consist of tretinoin 45 mg/m2 po daily (25 mg/m2 in patients <20 years of age) for 15 days and ATO 0.15 mg/kg IV for 10 doses. Disease status will be monitored with serial analyses of peripheral blood samples using RT-PCR for PML-RARα mRNA. Patients will be followed until relapse, death, loss to follow-up, or removal from study.

Induction therapy can be given as an inpatient or outpatient. Consolidation and maintenance treatments will be given as an outpatient. Consolidation may also be given at the patient's local institution. Intrathecal cytarabine treatments will be administered as an outpatient.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy
• Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: Feb 1, 2021
• Actual Study Completion Date: Feb 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tretinoin and Arsenic Trioxide This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission.	Drug: Tretinoin and Arsenic Trioxide; See Detailed Description

Outcome Measures

Primary Outcome Measures

1. To Determine the Rate of Molecular Remission [4 years]

   after induction with combined tretinoin and ATO (along with idarubicin in patients with high-risk disease or who develop leukocytosis) in APL.

Secondary Outcome Measures

1. Participants Who Experienced a Complete Remission [4 years]

   after induction with tretinoin and ATO (with idarubicin in patients with high-risk disease or who develop leukocytosis).

2. To Determine the Proportion of Patients in Molecular Remission [4 years]

   after each course of postremission therapy.

3. To Determine the Disease-free and Event-free Survival of Patients [4 years]

   treated with this program.

4. To Determine the Toxicity of This Treatment Program [4 years]

   including the early death rate (within 30 days), the incidence of APL differentiation syndrome, the number and length of hospitalizations, the incidence of secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), and the effects of treatment on left ventricular ejection fraction (LVEF) Frequencies of toxicities based on the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 will be tabulated.

5. To Characterize the Differentiation of APL Cells During Treatment [4 years]

   with combined tretinoin and ATO using serial immunophenotyping studies of peripheral blood

6. Explore the in Vivo Induction of Telomerase-dependent Cell Death [4 years]

   by ATRA (Tretinoin) and ATO (Arsenic Trioxide). Bone marrow samples will be analyzed at baseline and at the time of clinical CR for telomerase activity, telomere length and TERT expression

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Previously untreated patients with a morphologic diagnosis of APL, confirmed by demonstration of t(15;17) using conventional cytogenetics OR florescence in situ hybridization (FISH), OR a positive RT-PCR assay for PML-RAR at the subject's local institution.

• Age ≥18 years. Karnofsky performance status of ≥ 60%.

• Adequate renal function as demonstrated by a serum creatinine ≤ 2.0 mg/dl or a creatinine clearance of > 60 ml/min.

• Adequate hepatic function as demonstrated by a bilirubin < 2.0 mg/dl (unless attributable to Gilbert's disease) and an alkaline phosphatase, AST, and ALT ≤ 2.5 times the upper limit of normal.

• Normal cardiac function as demonstrated by a left ventricular ejection fraction ≥ 50% on echocardiogram or MUGA scan.

• QTc ≤ 500 msec on baseline ECG.

• Negative serum pregnancy test in women of childbearing potential.

• Ability to swallow oral medication.

• Men and women of child-bearing potential must be willing to practice an effective method of birth control during treatment and at least 4 months after treatment is finished.

• Patients with central nervous system involvement by APL are eligible and may receive concomitant treatment with radiation therapy and/or intrathecal chemotherapy in accordance with standard medical practice.

Exclusion Criteria:

• Previous treatment for APL, except tretinoin, which may be given for up to 7 days prior to study entry.

• Active serious infections not controlled by antibiotics.

• Pregnant women or women who are breast-feeding.

• Concurrent active malignancy requiring immediate therapy.

• Clinically significant cardiac disease (NY Heart Association Class III or IV), including chronic arrhythmias, or pulmonary disease.

• Other serious or life-threatening conditions deemed unacceptable by the principal investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Southern California	Los Angeles	California	United States	90033
2	Northwestern University	Evanston	Illinois	United States	60208
3	National Heart, Lung, and Blood Institute (NIH)	Bethesda	Maryland	United States	20824
4	Memorial Sloan Kettering at Basking Ridge	Basking Ridge	New Jersey	United States	07920
5	Memorial Sloan Kettering Monmouth	Middletown	New Jersey	United States	07748
6	Memorial Sloan Kettering Cancer Center @ Suffolk	Commack	New York	United States	11725
7	Memorial Sloan Kettering Westchester	Harrison	New York	United States	10604
8	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
9	New York Presbyterian Hospital-Weill Medical College of Cornell University	New York	New York	United States	10065
10	Memorial Sloan Kettering at Mercy Medical Center	Rockville Centre	New York	United States
11	Cleveland Clinic	Cleveland	Ohio	United States	44195
12	Princess Margaret Hospital/Ontario Cancer Institute	Toronto	Ontario	Canada

Sponsors and Collaborators

• Memorial Sloan Kettering Cancer Center
• Northwestern University
• New York Presbyterian Hospital
• University of Southern California
• Princess Margaret Hospital, Canada
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Jae Park, MD, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 7, 2018

More Information

Additional Information:

• Memorial Sloan Kettering Cancer Center

Publications

None provided.

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT01404949
• Other Study ID Numbers: 11-040
• First Posted: Jul 28, 2011
• Last Update Posted: Nov 30, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by Memorial Sloan Kettering Cancer Center: Tretinoin; all-trans retinoic acid; ATRA; Vesanoid; Arsenic Trioxide; ATO; Trisenox; 11-040
• Additional relevant MeSH terms: Leukemia; Leukemia, Promyelocytic, Acute; Arsenic Trioxide; Tretinoin

Study Results

Participant Flow

Arm/Group Title	Tretinoin and Arsenic Trioxide
Arm/Group Description	This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission. Tretinoin and Arsenic Trioxide: See Detailed Description
Period Title: Overall Study
STARTED	17
COMPLETED	16
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Tretinoin and Arsenic Trioxide
Arm/Group Description	This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission. Tretinoin and Arsenic Trioxide: See Detailed Description
Overall Participants	17
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	54
Sex: Female, Male (Count of Participants)
Female	7 41.2%
Male	10 58.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	17 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 5.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 5.9%
White	15 88.2%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	17 100%

Outcome Measures

1. Primary Outcome

Title	To Determine the Rate of Molecular Remission
Description	after induction with combined tretinoin and ATO (along with idarubicin in patients with high-risk disease or who develop leukocytosis) in APL.
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	Tretinoin and Arsenic Trioxide
Arm/Group Description	This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission. Tretinoin and Arsenic Trioxide: See Detailed Description
Measure Participants	0

2. Secondary Outcome

Title	Participants Who Experienced a Complete Remission
Description	after induction with tretinoin and ATO (with idarubicin in patients with high-risk disease or who develop leukocytosis).
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tretinoin and Arsenic Trioxide
Arm/Group Description	This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission. Tretinoin and Arsenic Trioxide: See Detailed Description
Measure Participants	16
Count of Participants [Participants]	16 94.1%

3. Secondary Outcome

Title	To Determine the Proportion of Patients in Molecular Remission
Description	after each course of postremission therapy.
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	Tretinoin and Arsenic Trioxide
Arm/Group Description	This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission. Tretinoin and Arsenic Trioxide: See Detailed Description
Measure Participants	0

4. Secondary Outcome

Title	To Determine the Disease-free and Event-free Survival of Patients
Description	treated with this program.
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	Tretinoin and Arsenic Trioxide
Arm/Group Description	This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission. Tretinoin and Arsenic Trioxide: See Detailed Description
Measure Participants	0

5. Secondary Outcome

Title	To Determine the Toxicity of This Treatment Program
Description	including the early death rate (within 30 days), the incidence of APL differentiation syndrome, the number and length of hospitalizations, the incidence of secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), and the effects of treatment on left ventricular ejection fraction (LVEF) Frequencies of toxicities based on the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 will be tabulated.
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	Tretinoin and Arsenic Trioxide
Arm/Group Description	This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission. Tretinoin and Arsenic Trioxide: See Detailed Description
Measure Participants	0

6. Secondary Outcome

Title	To Characterize the Differentiation of APL Cells During Treatment
Description	with combined tretinoin and ATO using serial immunophenotyping studies of peripheral blood
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	Tretinoin and Arsenic Trioxide
Arm/Group Description	This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission. Tretinoin and Arsenic Trioxide: See Detailed Description
Measure Participants	0

7. Secondary Outcome

Title	Explore the in Vivo Induction of Telomerase-dependent Cell Death
Description	by ATRA (Tretinoin) and ATO (Arsenic Trioxide). Bone marrow samples will be analyzed at baseline and at the time of clinical CR for telomerase activity, telomere length and TERT expression
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	Tretinoin and Arsenic Trioxide
Arm/Group Description	This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission. Tretinoin and Arsenic Trioxide: See Detailed Description
Measure Participants	0

Adverse Events

Time Frame	1 year
Arm/Group Title	Tretinoin and Arsenic Trioxide
Arm/Group Description	This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission. Tretinoin and Arsenic Trioxide: See Detailed Description
All Cause Mortality
	Tretinoin and Arsenic Trioxide
	Affected / at Risk (%)	# Events
Total	2/17 (11.8%)
Serious Adverse Events
	Tretinoin and Arsenic Trioxide
	Affected / at Risk (%)	# Events
Total	7/17 (41.2%)
Blood and lymphatic system disorders
Febrile Neutropenia	1/17 (5.9%)
Cardiac disorders
Chest pain - cardiac	1/17 (5.9%)
Sinus tachycardia	1/17 (5.9%)
Gastrointestinal disorders
Abdominal pain	1/17 (5.9%)
Constipation	1/17 (5.9%)
Nausea	2/17 (11.8%)
Vomiting	1/17 (5.9%)
General disorders
Fever	6/17 (35.3%)
Infections and infestations
Skin infection	1/17 (5.9%)
Metabolism and nutrition disorders
Hyperkalemia	1/17 (5.9%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/17 (5.9%)
Psychiatric disorders
Confusion	1/17 (5.9%)
Delirium	1/17 (5.9%)
Renal and urinary disorders
Acute kidney injury	1/17 (5.9%)
Vascular disorders
Thromboembolic event	1/17 (5.9%)
Other (Not Including Serious) Adverse Events
	Tretinoin and Arsenic Trioxide
	Affected / at Risk (%)	# Events
Total	17/17 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	4/17 (23.5%)
Anemia	2/17 (11.8%)
Lymph node pain	1/17 (5.9%)
Thrombotic thrombocytopenic purpura	1/17 (5.9%)
Cardiac disorders
Electrocardiogram QT corrected interval prolonged	2/17 (11.8%)
Sinus tachycardia	2/17 (11.8%)
Cardiac disorders - Other, specify	1/17 (5.9%)
Myocarditis	1/17 (5.9%)
Ear and labyrinth disorders
Hearing impaired	1/17 (5.9%)
Tinnitus	1/17 (5.9%)
Eye disorders
Eye disorders - Other, specify	3/17 (17.6%)
Cataract	1/17 (5.9%)
Dry eye	1/17 (5.9%)
Gastrointestinal disorders
Mucositis oral	4/17 (23.5%)
Diarrhea	3/17 (17.6%)
Colitis	2/17 (11.8%)
Constipation	2/17 (11.8%)
Dysphagia	2/17 (11.8%)
Nausea	2/17 (11.8%)
Abdominal distension	1/17 (5.9%)
Dry mouth	1/17 (5.9%)
Oral pain	1/17 (5.9%)
Vomiting	1/17 (5.9%)
General disorders
Fatigue	4/17 (23.5%)
Edema limbs	1/17 (5.9%)
Gen disorders & admin site conditions Other, spec	1/17 (5.9%)
Hepatobiliary disorders
Portal vein thrombosis	1/17 (5.9%)
Infections and infestations
Infections and infestations - Other, specify	2/17 (11.8%)
Upper respiratory infection	1/17 (5.9%)
Urinary tract infection	1/17 (5.9%)
Injury, poisoning and procedural complications
Bruising	1/17 (5.9%)
Fall	1/17 (5.9%)
Investigations
Alkaline phosphatase increased	2/17 (11.8%)
Aspartate aminotransferase increased	2/17 (11.8%)
Lymphocyte count decreased	2/17 (11.8%)
Weight loss	2/17 (11.8%)
Alanine aminotransferase increase	1/17 (5.9%)
Blood bilirubin increased	1/17 (5.9%)
Cholesterol high	1/17 (5.9%)
Investigation - Other, specify	1/17 (5.9%)
Platelet count decreased	1/17 (5.9%)
White blood cell decreased	1/17 (5.9%)
Metabolism and nutrition disorders
Hyperglycemia	3/17 (17.6%)
Hypertriglyceridemia	2/17 (11.8%)
Hypokalemia	2/17 (11.8%)
Hypophosphatemia	2/17 (11.8%)
Anorexia	1/17 (5.9%)
Hypocalcemia	1/17 (5.9%)
Hyponatremia	1/17 (5.9%)
Musculoskeletal and connective tissue disorders
Neck pain	1/17 (5.9%)
Nervous system disorders
Headache	3/17 (17.6%)
Dizziness	1/17 (5.9%)
Lethargy	1/17 (5.9%)
Paresthesia	1/17 (5.9%)
Peripheral motor neuropathy	1/17 (5.9%)
Psychiatric disorders
Depression	1/17 (5.9%)
Insomnia	1/17 (5.9%)
Psychiatric disorders - Other, specify	1/17 (5.9%)
Reproductive system and breast disorders
Erectile dysfunction	1/17 (5.9%)
Vaginal hemorrhage	1/17 (5.9%)
Respiratory, thoracic and mediastinal disorders
Cough	1/17 (5.9%)
Dyspnea	1/17 (5.9%)
Epistaxis	1/17 (5.9%)
Hypoxia	1/17 (5.9%)
Pulmonary edema	1/17 (5.9%)
Sinus pain	1/17 (5.9%)
Skin and subcutaneous tissue disorders
Dry skin	4/17 (23.5%)
Nail ridging	2/17 (11.8%)
Skin & subcutaneous tissue disordered Others, spec	2/17 (11.8%)
Alopecia	1/17 (5.9%)
Erythema multiforme	1/17 (5.9%)
Photosensitivity	1/17 (5.9%)
Rash acneiform	1/17 (5.9%)
Rash maculo-papular	1/17 (5.9%)
Vascular disorders
Hypertension	1/17 (5.9%)
Superficial thrombophlebitis	1/17 (5.9%)

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.