Treating Patients With Metastatic Prostate Cancer Not Responding to Hormone and Chemotherapy

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00331344
• Collaborator: (none)
• Enrollment: 100
• Locations: 2
• Arm: 1
• Duration (Months): 55
• Patients Per Site: 50
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This phase I/II trial is studying the side effects and best dose of ixabepilone and mitoxantrone hydrochloride when given together with prednisone and to see how well they work in treating patients with metastatic prostate cancer that did not respond to hormone therapy and chemotherapy. Drugs used in chemotherapy, such as ixabepilone, mitoxantrone hydrochloride, and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Prostate; Recurrent Prostate Cancer; Stage IV Prostate Cancer	Drug: mitoxantrone hydrochloride; Drug: ixabepilone; Drug: prednisone	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the maximum tolerated dose (MTD) and dose-limiting toxicities of the combination of ixabepilone, mitoxantrone hydrochloride, and prednisone in patients with hormone-refractory metastatic prostate cancer that progressed during or after taxane-based chemotherapy. (Phase I) II. Assess the efficacy, as measured by reduction in prostate-specific antigen, of this regimen in these patients. (Phase II)

SECONDARY OBJECTIVES:

1. Evaluate the overall safety of this regimen as second-line chemotherapy in these patients.

2. Evaluate the objective response rate in patients treated with this regimen.

OUTLINE: This is a multicenter, phase I, open label, dose-escalation study of mitoxantrone hydrochloride and ixabepilone followed by a phase II study.

PHASE I: Patients receive mitoxantrone hydrochloride intravenously (IV) over 30 minutes and ixabepilone IV over 3 hours on day 1 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of mitoxantrone hydrochloride and ixabepilone until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

PHASE II: Patients receive mitoxantrone hydrochloride and ixabepilone at the MTD determined in phase I and prednisone as in phase I.

After completion of study treatment, patients are followed every 3 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Trial of Epothilone Analog BMS-247550 (Ixabepilone), Mitoxantrone, and Prednisone in Hormone Refractory Prostate Cancer (HRPC) Patients Previously Treated With Chemotherapy
• Study Start Date: Apr 1, 2006
• Actual Primary Completion Date: Nov 1, 2010
• Actual Study Completion Date: Nov 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (combination chemotherapy) Patients receive mitoxantrone hydrochloride IV over 30 minutes and ixabepilone IV over 3 hours on day 1 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity.	Drug: mitoxantrone hydrochloride; Given IV; Other Names: CL 232315 DHAD DHAQ Novantrone ; Drug: ixabepilone; Given IV; Other Names: BMS-247550 epothilone B lactam Ixempra ; Drug: prednisone; Given orally; Other Names: DeCortin Deltra

Outcome Measures

Primary Outcome Measures

1. Proportion Responding to Treatment With of the Combination of Ixabepilone and Mitoxantrone Hydrochloride With Prednisone in Hormone Refractory Prostate Cancer Patients Who Have Had Prior Taxane Chemotherapy Based Upon a PSA Decline of > 50% (Phase II) [Every 3 courses until cancer progression/excessive toxicity or death]

   Descriptive statistics will be calculated to characterize the disease and treatment factors including the proportion responding with a 95% confidence interval. If accrual is completed and more than 15 of 58 patients show > 50% Prostate Specific Antigen (PSA) declines after 3 courses, then the null hypothesis of a 20% response proportion will be rejected. PSA declines for individual patients will be plotted in the form of a waterfall diagram of maximal PSA declines. 58 patients were enrolled for phase II, two were ineligible so 56 patients were analyzed.

2. Safety of the Combination of Ixabepilone, Mitoxantrone Hydrochloride, and Prednisone in Patients With Hormone-refractory Metastatic Prostate Cancer That Progressed During or After Taxane-based Chemotherapy (Phase I) [Every 21 days until cancer progression/excessive toxicity or death]

   This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 for adverse event monitoring and reporting. The cumulative grade 3 or higher adverse events for all dose levels are noted below and in the table of adverse events.

3. Dose Limiting Toxicities for Each Dose Level of Ixabepilone, Mitoxantrone Hydrochloride, and Prednisone in Patients With Hormone-refractory Metastatic Prostate Cancer That Progressed During or After Taxane-based Chemotherapy (Phase I). [Course 1 (first 21 days)]

   Cohorts of 3 patients will be enrolled at each dose level; if 1 dose limiting toxicity (DLT) is observed then the cohort will be expanded to 6 patients. If a second DLT is observed, the previous dose level will be considered the maximum tolerated dose (MTD). If all observed DLT are due to neuropathy (specific to ixabepilone), then we would consider the previous dose level of Ixabepilone the MTD for that drug, and escalate mitoxantrone hydrochloride as described above to a maximum dose of 12 mg/m^2. Toxicities will be tabulated by grade for each dose cohort and overall for all patients accrued to the phase I study.

Secondary Outcome Measures

1. Time to Progression (Phase II) [Every 3 months until cancer progression/excessive toxicity or death]

   Measured from the start of protocol therapy until RECIST (Response Evaluation Criteria In Solid Tumors Criteria) v1.0 progression. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the prostate

• Progressive metastatic disease (i.e., positive bone scan or measurable disease) despite castrate levels of testosterone (either from orchiectomy or luteinizing hormone-releasing hormone [LHRH] agonist therapy)

• Progressive disease after discontinuing hormonal therapy

• Progressive disease is based on any of the following*:

• Transaxial imaging

• Rise in prostate-specific antigen (PSA)

• Radionuclide bone scan (must show new metastatic lesions)

• Nonmeasurable or measurable disease

• For measurable disease, progression is defined by RECIST criteria

• Positive bone scan and elevated PSA required for nonmeasurable disease

• PSA evidence of progressive prostate cancer during or after first-line chemotherapy consists of a PSA level ≥ 2 ng/mL that has risen on ≥ 2 successive occasions ≥ 1 week apart

• Received ≥ 3 prior courses of paclitaxel- or docetaxel-based therapy, with disease progression documented during therapy or after cessation of therapy

• No more than 1 prior chemotherapy regimen

• Re-treatment with the same taxane-based regimen allowed

• Changes in prior chemotherapy regimen (addition of other agents) for disease progression are considered 2 chemotherapy regimens, and are not allowed

• PSA ≥ 2 ng/mL

• Testosterone < 50 ng/dL

• Patients must continue primary androgen deprivation with LHRH analogue if they have not undergone orchiectomy

• No known active brain metastases

• ECOG performance status 0-2

• Life expectancy ≥ 12 weeks

• Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance > 40 mL/min

• ALT and AST < 2.5 times ULN

• Granulocyte count ≥ 2,000/mm³

• Platelet count ≥ 100,000/mm³

• Bilirubin < 1.5 times ULN

• Ejection fraction normal by MUGA scan or echocardiogram

• No significant cardiovascular disease, including any of the following:

• Congestive heart failure (New York Heart Association class III-IV heart disease)

• Active angina pectoris

• Myocardial infarction within the past 6 months

• No serious infections or nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by study therapy

• No psychiatric illness or social situation that would preclude study compliance

• No pre-existing motor or sensory peripheral neuropathy > grade 1

• No known prior severe hypersensitivity reactions to agents containing Cremophor® EL

• No "currently active" second malignancy other than nonmelanoma skin cancer

• Patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered to be at < 30% risk of relapse

• Fertile patients must use effective contraception prior to, during, and for 3 months after completion of study treatment

• See Disease Characteristics

• No prior mitoxantrone hydrochloride, ixabepilone, or other epothilones

• At least 4 weeks since prior hormonal therapy (i.e., any dose of megestrol, finasteride, or any herbal product known to decrease PSA levels [e.g., saw palmetto or PC-SPES]) other than LHRH agonist or a stable dose of corticosteroids from a prior chemotherapy regimen

• More than 4 weeks since other prior systemic therapies for prostate cancer

• At least 4 weeks since prior radiation therapy

• More than 8 weeks since prior radiopharmaceuticals (e.g., strontium chloride Sr 89 or samarium Sm 153 lexidronam pentasodium)

• No concurrent moderate to strong CYP3A4 inhibitors

• No concurrent prophylactic colony-stimulating factors

• No concurrent radiotherapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94143-0875
2	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Andrea Harzstark, University of California San Francisco Medical Center-Mount Zion

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00331344
• Other Study ID Numbers: NCI-2009-00155; 055513; CDR0000481121; N01CM62202; NCT01648374
• First Posted: May 31, 2006
• Last Update Posted: Oct 31, 2017
• Last Verified: Oct 1, 2017

• Additional relevant MeSH terms: Prostatic Neoplasms; Prednisone; Mitoxantrone; Epothilone B; Epothilones

Study Results

Participant Flow

Recruitment Details	Patients (incl. currently followed in these practices, as well as those referred from outside providers) will be screened for interest and eligibility by medical oncologists from UCSF Urologic Oncology Practice CCC, UCSF-VA Medical Cntr, OHSU Cancer Inst., MD Anderson Cancer Cntr, UMich Comprehensive Cancer Cntr and the Portland VA Medical Cntr.

Arm/Group Title	Phase I Group I	Phase I Group II	Phase I Group III	Phase I Group IV	Phase I Group V	Phase I Group VI	Phase I Group Va	Phase I Group VIa	Phase II
Arm/Group Description	Patients receive mitoxantrone hydrochloride 8mg/m2 IV over 30 minutes and ixabepilone 20mg/m2 IV over 3 hours on day 1 and oral prednisone 5mg twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV prednisone: Given orally	Patients receive mitoxantrone hydrochloride 8mg/m2 IV over 30 minutes and ixabepilone 25mg/m2 IV over 3 hours on day 1 and oral prednisone 5mg twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV prednisone: Given orally	Patients receive mitoxantrone hydrochloride 10mg/m2 IV over 30 minutes and ixabepilone 25mg/m2 IV over 3 hours on day 1 and oral prednisone 5mg twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV prednisone: Given orally	Patients receive mitoxantrone hydrochloride 10mg/m2 IV over 30 minutes and ixabepilone 30mg/m2 IV over 3 hours on day 1 and oral prednisone 5mg twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV prednisone: Given orally	Patients receive mitoxantrone hydrochloride 12mg/m2 IV over 30 minutes and ixabepilone 30mg/m2 IV over 3 hours on day 1 and oral prednisone 5mg twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV prednisone: Given orally	Patients receive mitoxantrone hydrochloride 12mg/m2 IV over 30 minutes and ixabepilone 35mg/m2 IV over 3 hours on day 1 and oral prednisone 5mg twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV prednisone: Given orally	Patients receive mitoxantrone hydrochloride 12mg/m2 IV over 30 minutes and ixabepilone 30mg/m2 IV over 3 hours on day 1 and pegfilgrastim 6mg SC on day 2 and oral prednisone 5mg twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV pegfilgrastim: Given SC prednisone: Given orally	Patients receive mitoxantrone hydrochloride 12mg/m2 IV over 30 minutes and ixabepilone 35mg/m2 IV over 3 hours on day 1 and pegfilgrastim 6mg SC on day 2 and oral prednisone 5mg twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV pegfilgrastim: Given SC prednisone: Given orally	Patients receive mitoxantrone hydrochloride 12mg/m2 IV over 30 minutes and ixabepilone 30mg/m2 IV over 3 hours on day 1 and pegfilgrastim 6mg SC on day 2 and oral prednisone 5mg twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV pegfilgrastim: Given SC prednisone: Given orally
Period Title: Phase I
STARTED	3	3	3	6	6	5	4	6	0
COMPLETED	3	3	3	5	4	3	4	5	0
NOT COMPLETED	0	0	0	1	2	2	0	1	0
Period Title: Phase I
STARTED	0	0	0	0	0	0	0	6	52
COMPLETED	0	0	0	0	0	0	0	6	48
NOT COMPLETED	0	0	0	0	0	0	0	0	4

Baseline Characteristics

Arm/Group Title	Treatment (Combination Chemotherapy)
Arm/Group Description	Patients receive mitoxantrone hydrochloride IV over 30 minutes and ixabepilone IV over 3 hours on day 1 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV prednisone: Given orally
Overall Participants	88
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	38 43.2%
>=65 years	50 56.8%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	66.7
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	88 100%
Region of Enrollment (Count of Participants)
United States	88 100%

Outcome Measures

1. Primary Outcome

Title	Proportion Responding to Treatment With of the Combination of Ixabepilone and Mitoxantrone Hydrochloride With Prednisone in Hormone Refractory Prostate Cancer Patients Who Have Had Prior Taxane Chemotherapy Based Upon a PSA Decline of > 50% (Phase II)
Description	Descriptive statistics will be calculated to characterize the disease and treatment factors including the proportion responding with a 95% confidence interval. If accrual is completed and more than 15 of 58 patients show > 50% Prostate Specific Antigen (PSA) declines after 3 courses, then the null hypothesis of a 20% response proportion will be rejected. PSA declines for individual patients will be plotted in the form of a waterfall diagram of maximal PSA declines. 58 patients were enrolled for phase II, two were ineligible so 56 patients were analyzed.
Time Frame	Every 3 courses until cancer progression/excessive toxicity or death

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Combination Chemotherapy)
Arm/Group Description	Patients receive mitoxantrone hydrochloride 12mg/m2 IV over 30 minutes and ixabepilone 35mg/m2 IV over 3 hours on day 1 and pegfilgrastim 6mg SC on day 2 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV pegfilgrastim: Given SC prednisone: Given orally
Measure Participants	56
Count of Participants [Participants]	25 28.4%

2. Primary Outcome

Title	Safety of the Combination of Ixabepilone, Mitoxantrone Hydrochloride, and Prednisone in Patients With Hormone-refractory Metastatic Prostate Cancer That Progressed During or After Taxane-based Chemotherapy (Phase I)
Description	This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 for adverse event monitoring and reporting. The cumulative grade 3 or higher adverse events for all dose levels are noted below and in the table of adverse events.
Time Frame	Every 21 days until cancer progression/excessive toxicity or death

Outcome Measure Data

Analysis Population Description

Phase I dose escalation study participants

Arm/Group Title	Phase I Treatment (Groups I-VIa)
Arm/Group Description	Patients receive mitoxantrone hydrochloride 8-12mg/m2 IV over 30 minutes and ixabepilone 20-35mg/m2 IV over 3 hours on day 1 and oral prednisone twice daily on days 1-21. Patients in groups Va and VIa also received pegfilgrastim 6mg SC on day 2. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV pegfilgrastim: Given SC prednisone: Given orally
Measure Participants	36
Number [Adverse Events (above threshold)]	62

3. Primary Outcome

Title	Dose Limiting Toxicities for Each Dose Level of Ixabepilone, Mitoxantrone Hydrochloride, and Prednisone in Patients With Hormone-refractory Metastatic Prostate Cancer That Progressed During or After Taxane-based Chemotherapy (Phase I).
Description	Cohorts of 3 patients will be enrolled at each dose level; if 1 dose limiting toxicity (DLT) is observed then the cohort will be expanded to 6 patients. If a second DLT is observed, the previous dose level will be considered the maximum tolerated dose (MTD). If all observed DLT are due to neuropathy (specific to ixabepilone), then we would consider the previous dose level of Ixabepilone the MTD for that drug, and escalate mitoxantrone hydrochloride as described above to a maximum dose of 12 mg/m^2. Toxicities will be tabulated by grade for each dose cohort and overall for all patients accrued to the phase I study.
Time Frame	Course 1 (first 21 days)

Outcome Measure Data

Analysis Population Description

Dose escalation safety study (Phase I)

Arm/Group Title	Phase I Group I	Phase Group II	Phase I Group III	Phase I Group IV	Phase I Group V	Phase I Group VI	Phase I Group Va	Phase I Group VIa
Arm/Group Description	Patients receive mitoxantrone hydrochloride 8 mg/m2 IV over 30 minutes and ixabepilone 20mg/m2 IV over 3 hours on day 1 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV prednisone: Given orally	Patients receive mitoxantrone hydrochloride 8 mg/m2 IV over 30 minutes and ixabepilone 25mg/m2 IV over 3 hours on day 1 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV prednisone: Given orally	Patients receive mitoxantrone hydrochloride 10 mg/m2 IV over 30 minutes and ixabepilone 25 mg/m2 IV over 3 hours on day 1 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV prednisone: Given orally	Patients receive mitoxantrone hydrochloride 10 mg/m2 IV over 30 minutes and ixabepilone 30mg/m2 IV over 3 hours on day 1 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV prednisone: Given orally	Patients receive mitoxantrone hydrochloride 12 mg/m2 IV over 30 minutes and ixabepilone 30mg/m2 IV over 3 hours on day 1 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV prednisone: Given orally	Patients receive mitoxantrone hydrochloride 12 mg/m2 IV over 30 minutes and ixabepilone 35mg/m2 IV over 3 hours on day 1 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV prednisone: Given orally	Patients receive mitoxantrone hydrochloride 12 mg/m2 IV over 30 minutes and ixabepilone 30mg/m2 IV over 3 hours on day 1 and pegfilgrastim 6mg SC on day 2 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV pegfilgrastim: Given SC prednisone: Given orally	Patients receive mitoxantrone hydrochloride 12 mg/m2 IV over 30 minutes and ixabepilone 35mg/m2 IV over 3 hours on day 1 and pegfilgrastim 6mg SC on day 2 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV pegfilgrastim: Given SC prednisone: Given orally
Measure Participants	3	3	3	6	6	5	4	6
Count of Participants [Participants]	0 0%	0 NaN	0 NaN	1 NaN	2 NaN	2 NaN	0 NaN	1 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment (Combination Chemotherapy), Phase I Group III, Phase I Group IV, Phase I Group V, Phase I Group VI, Phase I Group Va, Phase I Group VIa
	Comments	Cohorts of 3 patients will be enrolled at each dose level; if 1 dose limiting toxicity (DLT) is observed then the cohort will be expanded to 6 patients. If a second DLT is observed, the previous dose level will be considered the MTD. If all observed DLT are due to neuropathy (specific to ixabepilone), then we would consider the previous dose level of Ixabepilone the MTD for that drug, and escalate mitoxantrone hydrochloride as described above to a maximum dose of 12 mg/m^2.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Dose Level VIa
	Estimated Value	1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Dose level VIa (mitoxantrone hydrochloride 12 mg/m2 IV over 30 minutes, ixabepilone 30mg/m2 IV over 3 hours on day 1, pegfilgrastim 6mg SC on day 2, oral prednisone twice daily on days 1-21) was determined to be MTD, based on 1 event of DLT at VIa.

4. Secondary Outcome

Title	Time to Progression (Phase II)
Description	Measured from the start of protocol therapy until RECIST (Response Evaluation Criteria In Solid Tumors Criteria) v1.0 progression. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	Every 3 months until cancer progression/excessive toxicity or death

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Combination Chemotherapy)
Arm/Group Description	Patients receive mitoxantrone hydrochloride 12mg/m2 IV over 30 minutes and ixabepilone 35mg/m2 IV over 3 hours on day 1 and pegfilgrastim 6mg SC on day 2 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV pegfilgrastim: Given SC prednisone: Given orally
Measure Participants	56
Median (95% Confidence Interval) [months]	4.4

Adverse Events

Arm/Group Title	Phase I and Phase II (Cumulative)
Arm/Group Description	Patients in the Phase I period receive mitoxantrone hydrochloride 8-12mg/m2 IV over 30 minutes and ixabepilone 20-35mg/m2 IV over 3 hours on day 1 and oral prednisone twice daily on days 1-21. Patients in groups Va and VIa also received pegfilgrastim 6mg SC on day 2. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. Patients in Phase II receive mitoxantrone hydrochloride 12mg/m2 IV over 30 minutes and ixabepilone 35mg/m2 IV over 3 hours on day 1 and pegfilgrastim 6mg SC on day 2 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. Adverse Events below are reported cumulatively for the entire study. mitoxantrone hydrochloride: Given IV ixabepilone: Given IV pegfilgrastim: Given SC prednisone: Given orally
All Cause Mortality
	Phase I and Phase II (Cumulative)
	Affected / at Risk (%)	# Events
Total	29/88 (33%)
Serious Adverse Events
	Phase I and Phase II (Cumulative)
	Affected / at Risk (%)	# Events
Total	19/88 (21.6%)
Blood and lymphatic system disorders
Leucocytes	3/88 (3.4%)
Neutrophil count decreased	4/88 (4.5%)
Platelet count decreased	1/88 (1.1%)
Febrile Neutropenia	1/88 (1.1%)
Cardiac disorders
Atrial fibrillation	3/88 (3.4%)
Cardiac ischemia/infarction	2/88 (2.3%)
Vasovagal episode	1/88 (1.1%)
Endocrine disorders
Adrenal Insuffiency	3/88 (3.4%)
Glucose intolerance	1/88 (1.1%)
Gastrointestinal disorders
Diarrhea	1/88 (1.1%)
Infections and infestations
Infection (limb)	1/88 (1.1%)
Pneumonia	1/88 (1.1%)
Methicillin-resistant Staphylococcus aureus	1/88 (1.1%)
Metabolism and nutrition disorders
Renal Failure	2/88 (2.3%)
Dehydration	1/88 (1.1%)
Renal and urinary disorders
Infection (Prostate)	1/88 (1.1%)
Sepsis	1/88 (1.1%)
Vascular disorders
Deep Vein Thrombosis	1/88 (1.1%)
Other (Not Including Serious) Adverse Events
	Phase I and Phase II (Cumulative)
	Affected / at Risk (%)	# Events
Total	56/88 (63.6%)
Blood and lymphatic system disorders
Hemoglobin	4/88 (4.5%)
Leucocytes	17/88 (19.3%)
Lymphopenia	20/88 (22.7%)
Neutrophil count decreased	12/88 (13.6%)
Platelet count decreased	9/88 (10.2%)
Edema, limb	1/88 (1.1%)
Cardiac disorders
Atrial tachycardia	1/88 (1.1%)
Endocrine disorders
Adrenal insufficiency	8/88 (9.1%)
Hot Flashes	1/88 (1.1%)
Gastrointestinal disorders
Nausea	5/88 (5.7%)
Dehydration	2/88 (2.3%)
Diarrhea	2/88 (2.3%)
Dyspepsia	1/88 (1.1%)
Vomiting	3/88 (3.4%)
General disorders
Fatigue	16/88 (18.2%)
Pain, other	2/88 (2.3%)
Pain, hip	1/88 (1.1%)
Anorexia	1/88 (1.1%)
Weight Loss	2/88 (2.3%)
Immune system disorders
Allergic Reaction	1/88 (1.1%)
Infections and infestations
Infection, Colon	1/88 (1.1%)
Pneumonia	5/88 (5.7%)
Infection, Skin	4/88 (4.5%)
Fever	1/88 (1.1%)
Phlebitis	1/88 (1.1%)
Metabolism and nutrition disorders
Alanine aminotransferase increased	1/88 (1.1%)
Hypocalcemia	2/88 (2.3%)
Hyponatremia	1/88 (1.1%)
Hyperbilirubinemia	1/88 (1.1%)
Hyperkalemia	1/88 (1.1%)
Hypoalbuminemia	1/88 (1.1%)
Hypophosphatemia	1/88 (1.1%)
Musculoskeletal and connective tissue disorders
Pain, bone	2/88 (2.3%)
Muscle Weakness	2/88 (2.3%)
Nervous system disorders
Peripheral sensory neuropathy	13/88 (14.8%)
Dizziness	2/88 (2.3%)
Peripheral Motor Neuropathy	2/88 (2.3%)
Syncope	1/88 (1.1%)
Taste Alteration	2/88 (2.3%)
Respiratory, thoracic and mediastinal disorders
Pain, Chest	3/88 (3.4%)
Dyspnea	3/88 (3.4%)
Hypoxia	1/88 (1.1%)
Acute Respiratory Distress Syndrome	1/88 (1.1%)
Pleural Effusion	1/88 (1.1%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.