Idarubicin + Cytarabine and Lenalidomide in Patients With Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML)

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00831766
• Collaborator: Celgene (Industry)
• Enrollment: 51
• Locations: 2
• Arms: 2
• Actual Duration (Months): 136.7
• Patients Per Site: 25.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to:

• Test the safety of the research study drug, lenalidomide, when given with Idarubicin and Cytarabine

• See how many respond to combination treatment with lenalidomide, Idarubicin and Cytarabine

• See how long people respond to this combination therapy

• See how long people live after being treated with this combination of drugs

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndrome; Acute Myeloid Leukemia	Drug: Idarubicin; Drug: Cytarabine; Drug: Lenalidomide (Revlimid®)	Phase 1/Phase 2

Detailed Description

All three drugs are FDA approved to treat patients in the United States of America. Idarubicin and Cytarabine combination therapy is a standard treatment for patients with acute myeloid leukemia (AML). Lenalidomide is FDA approved to retreat patients with Multiple Myeloma or Myelodysplastic syndrome with a specific change in their DNA. Loss of a specific part of DNA is also seen in some patients with AML.

This is a phase 1/2, dose-escalation trial of Lenalidomide given in combination with idarubicin + cytarabine. During phase 1, we will enroll patients with AML involving del 5q31; 2) patients with MDS RAEB-2 associated with monosomy 5 or segmental deletion involving 5q31, either alone or with additional cytogenetic abnormalities, and 3) older patients with any type of karyotypic profile in whom an effective and reliable standard of care remains to be developed. All 3 groups of patients define a population of patients with very poor prognoses. Dose escalation of lenalidomide will use a standard 3x3 design. Dose escalation of Lenalidomide only will take place, while the doses of idarubicin and cytarabine will be constant. This trial will have an induction component, consolidation component, and maintenance component. Overall safety and MTD will be determined from the induction phase only.

During phase 2, we will enroll only patients with AML age ≥ 60 years. During phase 2, the efficacy of this combination of Lenalidomide + idarubicin + cytarabine, at the maximum tolerated dose (MTD) for Lenalidomide (determined during phase 1), will be tested.

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Study of Sequential Idarubicin + Cytarabine, Followed by Lenalidomide, in Patients With Myelodysplastic Syndrome (RAEB-2) or With Previously Untreated Acute Myeloid Leukemia
• Actual Study Start Date: Jun 25, 2009
• Actual Primary Completion Date: Feb 17, 2015
• Actual Study Completion Date: Nov 16, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase I: Dose Escalation Induction: A dose escalation plan for induction therapy using a standard 3x3 design with dose escalation of Lenalidomide only, to determine maximum tolerated dose (MTD). Idarubicin and cytarabine doses will be fixed. Idarubicin: 12 mg/m^2. Cytarabine: 200 mg/m^2. Lenalidomide: According to dose escalation levels. Level 1: 5 mg/d; Level 2: 10 mg/d; Level 3: 15 mg/d; Level 4: 20 mg/d; Level 5: 25 mg/d.	Drug: Idarubicin; Intravenous infusion of Idarubicin as outlined in Phase I and Phase II Treatment Arms.; Other Names: Antineoplastic Agent ; Drug: Cytarabine; Intravenous infusion of Idarubicin as outlined in Phase I and Phase II Treatment Arms.; Other Names: Antineoplastic Agent ; Drug: Lenalidomide (Revlimid®); Lenalidomide as outlined in Phase I and Phase II Treatment Arms.; Other Names: Revlimid®
Experimental: Phase II: Treatment at MTD Idarubicin: 12 mg/m^2. Cytarabine: 200 mg/m^2. Lenalidomide: Maximum Tolerated Dose (MTD).	Drug: Idarubicin; Intravenous infusion of Idarubicin as outlined in Phase I and Phase II Treatment Arms.; Other Names: Antineoplastic Agent ; Drug: Cytarabine; Intravenous infusion of Idarubicin as outlined in Phase I and Phase II Treatment Arms.; Other Names: Antineoplastic Agent ; Drug: Lenalidomide (Revlimid®); Lenalidomide as outlined in Phase I and Phase II Treatment Arms.; Other Names: Revlimid®

Outcome Measures

Primary Outcome Measures

1. Phase I: Recommended Phase II Dose [18 months]

   For the Phase I component, no formal statistical analysis was planned. The primary endpoint is to determine the maximum tolerated dose (MTD) and recommended Phase II dose of lenalidomide given in combination with standard idarubicin + cytarabine induction therapy.

2. Phase II: Complete Response Rate of Participants Treated at Maximum Tolerated Dose (MTD) [24 months]

   Percentage of participants achieving CR/CRi. Complete Response (CR) plus Complete Response with Incomplete Count Recovery (CRi) rates. Response rates (CR + CRi) of lenalidomide following idarubicin and cytarabine induction therapy in older patients with previously untreated AML. A CR designation requires that the patient achieve the morphologic leukemia-free state and have an absolute neutrophil count of more than 1,000/μL and platelets of 100,000/μL. CRi: After chemotherapy, patients fulfill all of the criteria for CR except for residual neutropenia (1,000/μL) or thrombocytopenia (100,000/μL).

Secondary Outcome Measures

1. Rate of Lenalidomide Related Toxicity During Maintenance Therapy [24 months]

   Rate of toxicities of lenalidomide as maintenance therapy according to the National Cancer Institute Common Toxicity Criteria (CTC) V3. Adverse Events: Possibly Related; Probably Related, or Definitely Related to study treatment. Events are categorized as Grade 1 or 2, or as Grade 3 or 4.

2. Median Progression-Free Survival (PFS) [24 months]

   Progression-free survival (PFS), defined as the time from study entry to disease progression, relapse, or death due to any cause, whichever is earlier, will be summarized with the Kaplan-Meier curve.

3. Median Overall Survival (OS) [Up to 24 Months]

   Overall Survival (OS), defined for those patients who have achieved CR or CRi as the time from study entry to disease progression, relapse or death due to any cause, whichever is earlier, to be analyzed similarly. Descriptive analysis was planned for this measure.

Other Outcome Measures

1. Rate of Cytogenetic Remission Following Induction Therapy [24 Months]

   Rate of cytogenetic remission following induction therapy. Descriptive analysis was planned for this measure.

2. Median Relapse-Free Survival (RFS) [24 Months]

   Relapse-Free Survival (RFS), defined for those patients who have achieved CR or CRi as the time from study entry to disease progression, relapse or death due to any cause, whichever is earlier, will be analyzed similarly. Descriptive analysis was planned for this measure.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Understand and voluntarily sign an informed consent form

• Able to adhere to the study visit schedule and other protocol requirements

• Disease-specific criteria (Phase I):

• Previously untreated Acute Myeloid Leukemia (AML), associated with monosomy 5 or segmental deletion involving 5q31, either alone or with additional cytogenetic abnormalities

• Previously untreated AML (age ≥ 60 years)

• Myelodysplastic Syndrome, Refractory Anemia with Excess Blasts-2 (MDS,RAEB-2, 10-19% blasts in the bone marrow) associated with monosomy 5 or segmental deletion involving 5q31, either alone or with additional cytogenetic abnormalities

• For MDS, patients must have had progression with or failed response to front-line therapy with a nucleoside analogue (azacitidine, decitabine).

• Disease Specific Criteria (Phase II)

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 at study entry

• Left ventricular ejection fraction (LVEF) ≥ 50%

• Laboratory test results within these ranges:

• Serum creatinine ≤ 2.0 mg/dL

• Total bilirubin ≤ 1.5 mg/dL (Gilbert's syndrome excluded)

• Aspartic transaminase (AST) and Alanine transaminase (ALT) ≤ 2 x upper limit of normal (ULN)

• Disease free of prior malignancies for ≥ 2 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "insitu" of the cervix or breast

• Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting lenalidomide. For FCBP who have a medical need to proceed with therapy immediately, the pregnancy test that would normally be done 10-14 days prior to initiation of lenalidomide may be done as late as 7 days prior to initiation of lenalidomide. Both this test and the pregnancy testing done within 24 hours prior to initiation of lenalidomide must be negative. FCBP must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex* condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. *For patients who have latex allergies or whose partner(s) have latex allergies, alternatives will be discussed.

• Must be able to swallow capsules and no evidence of gastrointestinal (GI) tract abnormality that would alter absorption of oral medications

• Understand and voluntarily sign an informed consent form

• Life expectancy >3 months

• All study patients must be registered into the mandatory RevAssist® program and be willing and able to comply with the requirements of RevAssist®.

• Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days as required by RevAssist) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. See Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.

Exclusion Criteria:

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the informed consent form

• Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide).

• Unwilling or unable to participate with Food and Drug Administration (FDA) mandated birth control and pregnancy guidelines

• Any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study

• Use of any other experimental drug or therapy within 28 days of baseline

• Known hypersensitivity to thalidomide

• The development of erythema nodosum, if characterized by a desquamating rash, while taking thalidomide or similar drugs

• Any prior use of lenalidomide

• AML with cytogenetics including t(15;17), t(8;21), or inv(16)

• White blood count (WBC) count ≥ 50,000 on hydroxyurea therapy

• Previous history of induction chemotherapy for AML or allogeneic stem cell transplant

• Predicted inability to tolerate standard induction chemotherapy with idarubicin and cytarabine

• History of spontaneous thromboembolic event requiring use of anticoagulation with warfarin (coumadin) or low molecular-weight heparin within 3 years

• Known positive for human immunodeficiency virus (HIV) or infectious hepatitis, type A, B or C

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
2	Cleveland Clinic - Taussig Cancer Institute	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute
• Celgene

Investigators

• Principal Investigator: Jeffrey Lancet, M.D., H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT00831766
• Other Study ID Numbers: MCC-15625; RV-AML/MDS-PI-0269
• First Posted: Jan 29, 2009
• Last Update Posted: Dec 22, 2020
• Last Verified: Dec 1, 2020

• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: Hematopoietic; Myeloid and Monocytic Leukemia; AML
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Syndrome; Cytarabine; Lenalidomide; Idarubicin; Antineoplastic Agents

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at Moffitt Cancer Center and Cleveland Clinic between June 2009 and March 2014.

Arm/Group Title	Phase I: Dose Escalation	Phase II: Treatment at MTD
Arm/Group Description	Induction: A dose escalation plan for induction therapy using a standard 3x3 design with dose escalation of Lenalidomide only, to determine maximum tolerated dose (MTD). Idarubicin and cytarabine doses will be fixed. Idarubicin: 12 mg/m^2. Cytarabine: 200 mg/m^2. Lenalidomide: According to dose escalation levels. Level 1: 5 mg/d; Level 2: 10 mg/d; Level 3: 15 mg/d; Level 4: 20 mg/d; Level 5: 25 mg/d. Idarubicin: Intravenous infusion of Idarubicin as outlined in Phase I and Phase II Treatment Arms. Cytarabine: Intravenous infusion of Idarubicin as outlined in Phase I and Phase II Treatment Arms. Lenalidomide (Revlimid®): Lenalidomide as outlined in Phase I and Phase II Treatment Arms.	Idarubicin: 12 mg/m^2. Cytarabine: 200 mg/m^2. Lenalidomide: Maximum Tolerated Dose (MTD). Idarubicin: Intravenous infusion of Idarubicin as outlined in Phase I and Phase II Treatment Arms. Cytarabine: Intravenous infusion of Idarubicin as outlined in Phase I and Phase II Treatment Arms. Lenalidomide (Revlimid®): Lenalidomide as outlined in Phase I and Phase II Treatment Arms.
Period Title: Overall Study
STARTED	23	28
COMPLETED	23	28
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Phase I: Dose Escalation	Phase II: Treatment at MTD	Total
Arm/Group Description	Induction: A dose escalation plan for induction therapy using a standard 3x3 design with dose escalation of Lenalidomide only, to determine maximum tolerated dose (MTD). Idarubicin and cytarabine doses will be fixed. Idarubicin: 12 mg/m^2. Cytarabine: 200 mg/m^2. Lenalidomide: According to dose escalation levels. Level 1: 5 mg/d; Level 2: 10 mg/d; Level 3: 15 mg/d; Level 4: 20 mg/d; Level 5: 25 mg/d. Idarubicin: Intravenous infusion of Idarubicin as outlined in Phase I and Phase II Treatment Arms. Cytarabine: Intravenous infusion of Idarubicin as outlined in Phase I and Phase II Treatment Arms. Lenalidomide (Revlimid®): Lenalidomide as outlined in Phase I and Phase II Treatment Arms.	Idarubicin: 12 mg/m^2. Cytarabine: 200 mg/m^2. Lenalidomide: Maximum Tolerated Dose (MTD). Idarubicin: Intravenous infusion of Idarubicin as outlined in Phase I and Phase II Treatment Arms. Cytarabine: Intravenous infusion of Idarubicin as outlined in Phase I and Phase II Treatment Arms. Lenalidomide (Revlimid®): Lenalidomide as outlined in Phase I and Phase II Treatment Arms.	Total of all reporting groups
Overall Participants	23	28	51
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	8 34.8%	5 17.9%	13 25.5%
>=65 years	15 65.2%	23 82.1%	38 74.5%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	65	70	67.7
Sex: Female, Male (Count of Participants)
Female	5 21.7%	13 46.4%	18 35.3%
Male	18 78.3%	15 53.6%	33 64.7%
Region of Enrollment (participants) [Number]
United States	23 100%	28 100%	51 100%

Outcome Measures

1. Primary Outcome

Title	Phase I: Recommended Phase II Dose
Description	For the Phase I component, no formal statistical analysis was planned. The primary endpoint is to determine the maximum tolerated dose (MTD) and recommended Phase II dose of lenalidomide given in combination with standard idarubicin + cytarabine induction therapy.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

Phase I participants.

Arm/Group Title	Phase I Participants
Arm/Group Description	Dose escalation group.
Measure Participants	23
Number [mg/day]	20

2. Primary Outcome

Title	Phase II: Complete Response Rate of Participants Treated at Maximum Tolerated Dose (MTD)
Description	Percentage of participants achieving CR/CRi. Complete Response (CR) plus Complete Response with Incomplete Count Recovery (CRi) rates. Response rates (CR + CRi) of lenalidomide following idarubicin and cytarabine induction therapy in older patients with previously untreated AML. A CR designation requires that the patient achieve the morphologic leukemia-free state and have an absolute neutrophil count of more than 1,000/μL and platelets of 100,000/μL. CRi: After chemotherapy, patients fulfill all of the criteria for CR except for residual neutropenia (1,000/μL) or thrombocytopenia (100,000/μL).
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

All participants treated at MTD

Arm/Group Title	All Participants Treated at MTD
Arm/Group Description	All participants, regardless of Phase who were treated at the maximum tolerated dose (MTD).
Measure Participants	39
Number [percentage of participants]	54 234.8%

3. Secondary Outcome

Title	Rate of Lenalidomide Related Toxicity During Maintenance Therapy
Description	Rate of toxicities of lenalidomide as maintenance therapy according to the National Cancer Institute Common Toxicity Criteria (CTC) V3. Adverse Events: Possibly Related; Probably Related, or Definitely Related to study treatment. Events are categorized as Grade 1 or 2, or as Grade 3 or 4.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

All Maintenance Phase participants.

Arm/Group Title	Maintenance Phase Participants
Arm/Group Description	All participants treated in the Maintenance Phase.
Measure Participants	6
Leukocytes (total WBC) - low - Grade 1 or 2	1 4.3%
Leukocytes (total WBC) - low - Grade 3 or 4	0 0%
ANC/AGC - Grade 1 or 2	0 0%
ANC/AGC - Grade 3 or 4	1 4.3%
Platelets - low - Grade 1 or 2	3 13%
Platelets - low - Grade 3 or 4	0 0%
Fatigue - Grade 1 or 2	1 4.3%
Fatigue - Grade 3 or 4	0 0%
Dry skin - Grade 1 or 2	1 4.3%
Dry skin - Grade 3 or 4	0 0%
Pruritus/itching - Grade 1 or 2	1 4.3%
Pruritus/itching - Grade 3 or 4	0 0%
Rash/desquamation - Grade 1 or 2	2 8.7%
Rash/desquamation - Grade 3 or 4	0 0%
Constipation - Grade 1 or 2	1 4.3%
Constipation - Grade 3 or 4	0 0%
Diarrhea - Grade 1 or 2	2 8.7%
Diarrhea - Grade 3 or 4	0 0%
Nausea - Grade 1 or 2	1 4.3%
Nausea - Grade 3 or 4	0 0%
Ulcer, GI - Anus - Grade 1 or 2	1 4.3%
Ulcer, GI - Anus - Grade 3 or 4	0 0%
Hemorrhage, GI - Rectum - Grade 1 or 2	1 4.3%
Hemorrhage, GI - Rectum - Grade 3 or 4	0 0%
Infection - Skin (cellulitis) Grade 1 or 2	1 4.3%
Infection - Skin (cellulitis) Grade 3 or 4	0 0%
AST, SGOT - Grade 1 of 2	2 8.7%
AST, SGOT - Grade 3 or 4	0 0%
Pain - Head/headache - Grade 1 or 2	1 4.3%
Pain - Head/headache - Grade 3 or 4	0 0%

4. Secondary Outcome

Title	Median Progression-Free Survival (PFS)
Description	Progression-free survival (PFS), defined as the time from study entry to disease progression, relapse, or death due to any cause, whichever is earlier, will be summarized with the Kaplan-Meier curve.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

All participants treated at MTD.

Arm/Group Title	All Participants Treated at MTD
Arm/Group Description	All participants, regardless of Phase who were treated at the maximum tolerated dose (MTD).
Measure Participants	39
Median (95% Confidence Interval) [months]	7.55

5. Secondary Outcome

Title	Median Overall Survival (OS)
Description	Overall Survival (OS), defined for those patients who have achieved CR or CRi as the time from study entry to disease progression, relapse or death due to any cause, whichever is earlier, to be analyzed similarly. Descriptive analysis was planned for this measure.
Time Frame	Up to 24 Months

Outcome Measure Data

Analysis Population Description

All participants treated at MTD

Arm/Group Title	All Participants Treated at MTD
Arm/Group Description	All participants, regardless of Phase who were treated at the maximum tolerated dose (MTD).
Measure Participants	39
Median (95% Confidence Interval) [months]	11.22

6. Other Pre-specified Outcome

Title	Rate of Cytogenetic Remission Following Induction Therapy
Description	Rate of cytogenetic remission following induction therapy. Descriptive analysis was planned for this measure.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Median Relapse-Free Survival (RFS)
Description	Relapse-Free Survival (RFS), defined for those patients who have achieved CR or CRi as the time from study entry to disease progression, relapse or death due to any cause, whichever is earlier, will be analyzed similarly. Descriptive analysis was planned for this measure.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	4 years, 8 months
Adverse Event Reporting Description	All Serious Adverse Events (SAEs) are reported, regardless of causality. All Other (not including Serious) Adverse Events (AEs) meeting 5% frequency threshold are reported, regardless of causality.
Arm/Group Title	Phase I: Dose Escalation		Phase II: Treatment at MTD
Arm/Group Description	Participants enrolled during Phase I.		Participants enrolled during Phase II.
All Cause Mortality
	Phase I: Dose Escalation		Phase II: Treatment at MTD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase I: Dose Escalation		Phase II: Treatment at MTD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/23 (21.7%)		13/28 (46.4%)
Blood and lymphatic system disorders
Neutrophils/granulocytes - low	0/23 (0%)	0	1/28 (3.6%)	1
Platelets - low	0/23 (0%)	0	2/28 (7.1%)	2
Cardiac disorders
Cardiac Arrhythmia - Other, atrial fibrilation with rapid ventricular response	0/23 (0%)	0	1/28 (3.6%)	1
Supraventricular and nodal arrhythmai - atrial fibirillation	0/23 (0%)	0	1/28 (3.6%)	1
Cardiac ischemia/infarction	1/23 (4.3%)	1	0/28 (0%)	0
Left ventricular systolic dysfunction	1/23 (4.3%)	1	0/28 (0%)	0
Gastrointestinal disorders
Anorexia	0/23 (0%)	0	1/28 (3.6%)	1
Dehydration	0/23 (0%)	0	1/28 (3.6%)	1
Diarrhea	0/23 (0%)	0	2/28 (7.1%)	3
Mucositis/stomatitis - Oral cavity	1/23 (4.3%)	1	0/28 (0%)	0
General disorders
Fever (in the absence of neutropenia)	1/23 (4.3%)	1	1/28 (3.6%)	1
Death - Disease progression NOS	1/23 (4.3%)	1	0/28 (0%)	0
Death - Multi-organ failure	1/23 (4.3%)	1	0/28 (0%)	0
Pain - Extremity, limb	1/23 (4.3%)	1	0/28 (0%)	0
Infections and infestations
Febrile neutropenia	1/23 (4.3%)	1	9/28 (32.1%)	9
Infection with Grade 3 or 4 neutrophils - abdomen, NOS	0/23 (0%)	0	1/28 (3.6%)	1
Infection with Grade 3 or 4 neutrophils - Blood	0/23 (0%)	0	5/28 (17.9%)	5
Infection with Grade 3 or 4 neutrophils - Lung (pneumonia)	0/23 (0%)	0	1/28 (3.6%)	1
Infection with normal ANC or Grade 1 or 2 neutrophnils - Gallbladder (cholecystitis)	0/23 (0%)	0	1/28 (3.6%)	1
Infection with Grade 3 or 4 Neutrophils - Urinary Tract	0/23 (0%)	0	1/28 (3.6%)	1
Metabolism and nutrition disorders
AST, SGOT - high	1/23 (4.3%)	1	0/28 (0%)	0
Nervous system disorders
Confusion	0/23 (0%)	0	1/28 (3.6%)	1
Renal and urinary disorders
Renal/Genitourinary - Other, acute kidney injury	0/23 (0%)	0	1/28 (3.6%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/23 (4.3%)	1	0/28 (0%)	0
Vascular disorders
Thrombosis/embolism (vascular access-related)	0/23 (0%)	0	1/28 (3.6%)	1
Other (Not Including Serious) Adverse Events
	Phase I: Dose Escalation		Phase II: Treatment at MTD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/23 (95.7%)		26/28 (92.9%)
Blood and lymphatic system disorders
Platelets - low	16/23 (69.6%)	22	17/28 (60.7%)	40
Hemoglobin - low	9/23 (39.1%)	16	18/28 (64.3%)	31
Neutrophils/granulocytes - low	10/23 (43.5%)	12	14/28 (50%)	30
Leukocytes (total WBC) - low	2/23 (8.7%)	4	6/28 (21.4%)	16
Edema: limb	8/23 (34.8%)	11	18/28 (64.3%)	29
Edema: head and neck	0/23 (0%)	0	4/28 (14.3%)	4
Lymphatics - Other, fluid retention	1/23 (4.3%)	1	2/28 (7.1%)	2
Cardiac disorders
Hypotension	3/23 (13%)	4	8/28 (28.6%)	9
Hypertension	2/23 (8.7%)	2	7/28 (25%)	8
Pericardial effusion (non-malignant)	2/23 (8.7%)	2	0/28 (0%)	0
Ventricular arrhythmia - Ventricular tachycardia	0/23 (0%)	0	6/28 (21.4%)	8
Supraventricular and nodal arrhythmia - Sinus bradycardia	3/23 (13%)	3	2/28 (7.1%)	2
Supraventricular and nodal arrhythmia - Sinus tachycardia	1/23 (4.3%)	1	2/28 (7.1%)	2
Supraventricular and nodal arrhythmia - Atrial fibrillation	2/23 (8.7%)	2	0/28 (0%)	0
Eye disorders
Dry eye syndrome	2/23 (8.7%)	2	1/28 (3.6%)	1
Vision-blurred vision	0/23 (0%)	0	3/28 (10.7%)	3
Gastrointestinal disorders
Diarrhea	19/23 (82.6%)	31	25/28 (89.3%)	41
Nausea	12/23 (52.2%)	16	16/28 (57.1%)	33
Constipation	7/23 (30.4%)	7	17/28 (60.7%)	19
Anorexia	6/23 (26.1%)	7	16/28 (57.1%)	23
Mucositis/stomatitis (clinical exam) - Oral cavity	9/23 (39.1%)	11	13/28 (46.4%)	18
Vomiting	7/23 (30.4%)	8	15/28 (53.6%)	17
Distension/bloating, abdominal	1/23 (4.3%)	1	11/28 (39.3%)	17
Dry mouth/salivary gland (xerostomia)	1/23 (4.3%)	1	7/28 (25%)	7
Gastrointestinal - Other, GERD	0/23 (0%)	0	3/28 (10.7%)	3
Taste alteration (dysgeusia)	1/23 (4.3%)	1	5/28 (17.9%)	5
Heartburn/dyspepsia	2/23 (8.7%)	4	5/28 (17.9%)	11
Hemorrhoids	0/23 (0%)	0	5/28 (17.9%)	6
Colitis	2/23 (8.7%)	2	1/28 (3.6%)	1
Enteritis (inflammation of the small bowel)	2/23 (8.7%)	2	1/28 (3.6%)	1
Flatulence	0/23 (0%)	0	2/28 (7.1%)	2
Hemorrhage, G I- Oral cavity	2/23 (8.7%)	2	0/28 (0%)	0
General disorders
Pain - Abdomen NOS	10/23 (43.5%)	13	7/28 (25%)	9
Pain - Head/headache	1/23 (4.3%)	1	11/28 (39.3%)	12
Pain - Chest wall	3/23 (13%)	3	7/28 (25%)	8
Pain - back	2/23 (8.7%)	2	6/28 (21.4%)	6
Pain - Throat/pharynx/larynx	2/23 (8.7%)	3	6/28 (21.4%)	7
Pain - Chest/thorax NOS	1/23 (4.3%)	1	5/28 (17.9%)	5
Pain - Extremity-limb	1/23 (4.3%)	2	2/28 (7.1%)	3
Pain - Oral cavity	0/23 (0%)	0	3/28 (10.7%)	3
Fatigue	5/23 (21.7%)	6	14/28 (50%)	16
Rigors/chills	3/23 (13%)	4	13/28 (46.4%)	20
Insomnia	3/23 (13%)	3	10/28 (35.7%)	11
Fever (in the absence of neutropenia)	5/23 (21.7%)	6	14/28 (50%)	16
Sweating (diaphoresis)	1/23 (4.3%)	1	5/28 (17.9%)	6
Weight loss	3/23 (13%)	3	2/28 (7.1%)	2
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	0/23 (0%)	0	2/28 (7.1%)	2
Infections and infestations
Febrile neutropenia	14/23 (60.9%)	22	22/28 (78.6%)	39
Infection with Grade 3 or 4 neutrophils - Lung (pneumonia)	9/23 (39.1%)	12	5/28 (17.9%)	5
Infection with Grade 3 or 4 neutrophils - Blood	0/23 (0%)	0	9/28 (32.1%)	10
Infection with normal ANC or Grade 1 or 2 neutrophils - Skin (cellulitis)	1/23 (4.3%)	1	3/28 (10.7%)	3
Infection with Grade 3 or 4 neutrophils - Abdomen NOS	1/23 (4.3%)	1	2/28 (7.1%)	2
Infection with normal ANC or Grade 1 or 2 neutrophils - Blood	2/23 (8.7%)	2	1/28 (3.6%)	2
Infection with Grade 3 or 4 neutrophils - Bladder (urinary)	0/23 (0%)	0	2/28 (7.1%)	2
Infection with unknown ANC - Anal/perianal	0/23 (0%)	0	2/28 (7.1%)	2
Infection with unknown ANC - Lung (pneumonia)	1/23 (4.3%)	1	2/28 (7.1%)	2
Infection with unknown ANC - Skin (cellulitis)	0/23 (0%)	0	3/28 (10.7%)	3
Metabolism and nutrition disorders
ALT, SGPT - high	5/23 (21.7%)	6	7/28 (25%)	12
Bilirubin (hyperbilirubinemia)	4/23 (17.4%)	4	7/28 (25%)	11
Potassium, serum-low (hypokalemia)	4/23 (17.4%)	11	5/28 (17.9%)	5
Calcium, serum-low (hypocalcemia)	4/23 (17.4%)	5	6/28 (21.4%)	8
Sodium, serum-low (hyponatremia)	5/23 (21.7%)	7	3/28 (10.7%)	3
Albumin, serum-low (hypoalbuminemia)	6/23 (26.1%)	6	4/28 (14.3%)	8
AST, SGOT - high	3/23 (13%)	4	6/28 (21.4%)	7
Magnesium, serum-low (hypomagnesemia)	6/23 (26.1%)	8	2/28 (7.1%)	4
Potassium, serum-high (hyperkalemia)	6/23 (26.1%)	12	1/28 (3.6%)	1
Alkaline phosphatase - increased	3/23 (13%)	5	2/28 (7.1%)	4
Glucose, serum-high (hyperglycemia)	2/23 (8.7%)	2	3/28 (10.7%)	3
Creatinine - high	3/23 (13%)	4	0/28 (0%)	0
Phosphate, serum-low (hypophosphatemia)	0/23 (0%)	0	2/28 (7.1%)	2
Tumor lysis syndrome	2/23 (8.7%)	2	0/28 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy) - Whole body/generalized	4/23 (17.4%)	6	6/28 (21.4%)	6
Nervous system disorders
Dizziness	4/23 (17.4%)	5	12/28 (42.9%)	17
Confusion	1/23 (4.3%)	2	4/28 (14.3%)	4
Syncope (fainting)	2/23 (8.7%)	2	2/28 (7.1%)	2
Extrapyramidal/involuntary movement/restlessness	0/23 (0%)	0	2/28 (7.1%)	2
Memory impairment	0/23 (0%)	0	2/28 (7.1%)	2
Psychiatric disorders
Mood alteration - Anxiety	4/23 (17.4%)	4	8/28 (28.6%)	8
Psychosis (hallucinations/delusions)	0/23 (0%)	0	6/28 (21.4%)	6
Mental status - Change	0/23 (0%)	0	4/28 (14.3%)	4
Renal and urinary disorders
Renal/Genitourinary - Other, acute kidney injury	2/23 (8.7%)	2	0/28 (0%)	0
Renal failure	2/23 (8.7%)	2	0/28 (0%)	0
Urinary frequency/urgency	0/23 (0%)	0	3/28 (10.7%)	3
Urinary retention (including neurogenic bladder)	0/23 (0%)	0	2/28 (7.1%)	2
Renal/Genitourinary - Other, hematuria	3/23 (13%)	3	0/28 (0%)	0
Renal/Genitourinary - Other, renal insufficiency	2/23 (8.7%)	2	1/28 (3.6%)	1
Respiratory, thoracic and mediastinal disorders
Cough	8/23 (34.8%)	8	15/28 (53.6%)	19
Dyspnea (shortness of breath)	3/23 (13%)	3	13/28 (46.4%)	16
Pleural effusion (non-malignant)	4/23 (17.4%)	4	8/28 (28.6%)	8
Pulmonary/Upper Respiratory - Other, respiratory failure	1/23 (4.3%)	1	2/28 (7.1%)	2
Hypoxia	1/23 (4.3%)	1	5/28 (17.9%)	5
Bronchospasm, wheezing	0/23 (0%)	0	5/28 (17.9%)	5
Nasal cavity/paranasal sinus reactions	0/23 (0%)	0	4/28 (14.3%)	4
Pneumonitis/pulmonary infiltrates	2/23 (8.7%)	2	2/28 (7.1%)	2
Hemorrhage, pulmonary/upper respiratory - Nose	5/23 (21.7%)	6	9/28 (32.1%)	11
Hemorrhage, pulmonary/upper respiratory - Bronchopulmonary NOS	0/23 (0%)	0	2/28 (7.1%)	2
Allergic rhinitis	1/23 (4.3%)	1	4/28 (14.3%)	4
Skin and subcutaneous tissue disorders
Rash/desquamation	14/23 (60.9%)	25	19/28 (67.9%)	35
Pruritus/itching	6/23 (26.1%)	6	14/28 (50%)	18
Ulceration	0/23 (0%)	0	6/28 (21.4%)	9
Rash: erythema multiforme	0/23 (0%)	0	5/28 (17.9%)	5
Dry skin	0/23 (0%)	0	4/28 (14.3%)	4
Rash: acne/acneiform	2/23 (8.7%)	2	2/28 (7.1%)	2
Hair loss/alopecia (scalp or body)	0/23 (0%)	0	2/28 (7.1%)	2
Infection with Grade 3 or 4 neutrophils - Skin (cellulitis)	2/23 (8.7%)	2	4/28 (14.3%)	4
Infection with unknown ANC - Skin (cellulitis)	0/23 (0%)	0	2/28 (7.1%)	2
Infection with Grade 3 or 4 neutrophils - Anal/perianal	0/23 (0%)	0	2/28 (7.1%)	2
Petechiae/purpura (hrmorrhage/bldding into skin or mucosa)	3/23 (13%)	3	3/28 (10.7%)	4

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.