A Phase II Study of UCN-01 in Metastatic Melanoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00072189
• Collaborator: (none)
• Enrollment: 17
• Location: 1
• Arm: 1
• Duration (Months): 76
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

UCN-01 may stop the growth of tumor cells by blocking the enzymes necessary for their growth. This phase II trial is studying how well UCN-01 works in treating patients with metastatic melanoma.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Melanoma; Stage IV Melanoma	Drug: 7-hydroxystaurosporine; Other: laboratory biomarker analysis; Other: pharmacological study	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the anti-tumor activity of UCN-01 (7-hydroxystaurosporine) in metastatic melanoma, as determined by the response rate.

2. To assess the clinical and laboratory toxicities of UCN-01. III. To study the effects of UCN-01 administration on potential markers of specific G1-phase cell cycle regulators.

OUTLINE: This is a multicenter study.

Patients receive UCN-01 IV over 3 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients are followed for survival.

PROJECTED ACCRUAL: A total of 17-33 patients will be accrued for this study within 18 months.

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: A Phase II Study of UCN-01 in Metastatic Melanoma
• Study Start Date: Nov 1, 2003
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (7-hydroxystaurosporine) Patients receive UCN-01 IV over 3 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: 7-hydroxystaurosporine; Given IV; Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Response Rate [Up to 7 years]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Secondary Outcome Measures

1. Overall Survival [Up to 7 years]

   Estimated using the product-limit method of Kaplan and Meier.

2. Progression-free Survival [From the date of study registration to the first documentation of progressive tumor, assessed up to 7 years]

   Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), 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: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients have histologically or cytologically confirmed melanoma that is incurable by other means such as surgery, radiotherapy, or limb perfusion

• Patients must have measurable disease, defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 10 mm with conventional techniques or with spiral CT scan, and which has clearly progressed during the observation interval prior to participation in this study

• Patients must have received =< 1 prior chemotherapy and/or =< biological therapies; isolated limb perfusion with a biological and/or chemotherapeutic agent is allowed if the measurable disease and the lesion that will be biopsied for this protocol are outside the area of prior perfusion; at least 4 weeks must have elapsed since prior therapy (6 weeks for nitrosoureas or mitomycin C) and the patient must have recovered from all toxicities attributable to prior therapy

• Life expectancy greater than 4 months

• Eastern Cooperative Oncology Group (ECOG) performance status #2 (Karnofsky >= 60%)

• Leukocytes >= 3000/uL

• Absolute neutrophil count >= 1500/uL

• Platelets >= 100000/uL

• Total bilirubin =< 1.5 mg/dL

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 X institutional upper limit of normal

• Creatinine < 1.6 mg/dL

• Creatinine clearance >= 50 mL/min for patients with creatinine levels above 1.6 mg/dL

• The effects of UCN-01 on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• Ability to understand and willingness to sign a written informed consent document

• Patient must have a central venous catheter

• Patients are requested to submit archival tissue for pre-study and undergo a tumor biopsy 24 hours post UCN-01 administration if feasible

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or who have not recovered from adverse events to agents administered more than 4 weeks earlier

• Patients must not be receiving any other investigational agents

• Patients with known brain metastases are eligible only if disease is controlled and patient is asymptomatic (i.e. at least 4 weeks from completion of whole brain irradiation, stereotactic radiosurgery, or gamma knife irradiation) and not receiving corticosteroids

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to UCN-01

• Patients with only non-measurable disease, defined as all other lesions, including small lesions (longest diameter >= 10 mm with conventional techniques or with spiral

CT scan) and truly non-measurable lesions, which include the following:

• Bone lesions

• Leptomeningeal disease

• Ascites

• Pleural or pericardial effusion

• Abdominal masses that are not confirmed and followed by imaging techniques

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, systematic congestive heart failure, symptomatic pulmonary diseases, unstable angina pectoris, cardiac arrhythmia, prior mediastinal radiation or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant women are excluded from this study because UCN-01 is a serine-threonine kinase inhibitor with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse effects in nursing infants secondary to treatment of the mother with UCN-01, breastfeeding should be discontinued if the mother is treated with UCN-01

• Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with UCN-01; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated

• Due to the incidence of hyperglycemia with UCN-01, patients with a history of diabetes will be excluded from the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UC Davis Cancer Center	Sacramento	California	United States	95817

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Scott Christensen, MD, University of California, Davis

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00072189
• Other Study ID Numbers: NCI-2012-02829; NCI-2012-02829; PHII-33; 5536; N01CM17101
• First Posted: Nov 6, 2003
• Last Update Posted: Mar 2, 2015
• Last Verified: Oct 1, 2013

• Additional relevant MeSH terms: Melanoma; 7-hydroxystaurosporine

Study Results

Participant Flow

Arm/Group Title	Arm 1
Arm/Group Description	Patients receive UCN-01 IV at 90 mg/m2 over 3 hours on cycle 1, reduced to 45 mg/m2 over 3 hours for subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. 7-hydroxystaurosporine: Given IV laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies
Period Title: Overall Study
STARTED	17
COMPLETED	16
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Arm 1
Arm/Group Description	Patients receive UCN-01 IV at 90 mg/m2 over 3 hours on cycle 1, reduced to 45 mg/m2 over 3 hours for subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. 7-hydroxystaurosporine: Given IV laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies
Overall Participants	17
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	53
Sex: Female, Male (Count of Participants)
Female	11 64.7%
Male	6 35.3%
Region of Enrollment (participants) [Number]
United States	17 100%

Outcome Measures

1. Primary Outcome

Title	Response Rate
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time Frame	Up to 7 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1
Arm/Group Description	Patients receive UCN-01 IV at 90 mg/m2 over 3 hours on cycle 1, reduced to 45 mg/m2 over 3 hours for subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. 7-hydroxystaurosporine: Given IV laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies
Measure Participants	16
Number [percentage of responding participants]	0 0%

2. Secondary Outcome

Title	Overall Survival
Description	Estimated using the product-limit method of Kaplan and Meier.
Time Frame	Up to 7 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1
Arm/Group Description	Patients receive UCN-01 IV at 90 mg/m2 over 3 hours on cycle 1, reduced to 45 mg/m2 over 3 hours for subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. 7-hydroxystaurosporine: Given IV laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies
Measure Participants	17
Median (95% Confidence Interval) [months]	7.3

3. Secondary Outcome

Title	Progression-free Survival
Description	Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), 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	From the date of study registration to the first documentation of progressive tumor, assessed up to 7 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1
Arm/Group Description	Patients receive UCN-01 IV at 90 mg/m2 over 3 hours on cycle 1, reduced to 45 mg/m2 over 3 hours for subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. 7-hydroxystaurosporine: Given IV laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies
Measure Participants	17
Median (95% Confidence Interval) [months]	1.3

Adverse Events

Time Frame	Collected over a period of 24 months.
Adverse Event Reporting Description	"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Arm/Group Title	Arm 1
Arm/Group Description	Patients receive UCN-01 IV at 90 mg/m2 over 3 hours on cycle 1, reduced to 45 mg/m2 over 3 hours for subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. 7-hydroxystaurosporine: Given IV laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies
All Cause Mortality
	Arm 1
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm 1
	Affected / at Risk (%)	# Events
Total	7/17 (41.2%)
Blood and lymphatic system disorders
Hemoglobin decreased	1/17 (5.9%)	1
Packed red blood cell transfusion	1/17 (5.9%)	1
Cardiac disorders
Arrhythmia supraventricular	1/17 (5.9%)	2
Gastrointestinal disorders
Haematemesis	1/17 (5.9%)	1
Diarrhea	1/17 (5.9%)	1
General disorders
General symptom	2/17 (11.8%)	2
Investigations
Creatinine increased	1/17 (5.9%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/17 (11.8%)	2
Other (Not Including Serious) Adverse Events
	Arm 1
	Affected / at Risk (%)	# Events
Total	17/17 (100%)
Blood and lymphatic system disorders
Hemoglobin decreased	7/17 (41.2%)	16
Packed red blood cell transfusion	2/17 (11.8%)	2
Cardiac disorders
Arrhythmia supraventricular	1/17 (5.9%)	1
Sinus tachycardia	2/17 (11.8%)	2
Ear and labyrinth disorders
Hearing loss	1/17 (5.9%)	5
Middle ear inflammation	1/17 (5.9%)	2
Gastrointestinal disorders
Abdominal pain	3/17 (17.6%)	4
Constipation	2/17 (11.8%)	4
Diarrhea	2/17 (11.8%)	2
Dyspepsia	1/17 (5.9%)	1
Gastritis	1/17 (5.9%)	1
Nausea	11/17 (64.7%)	12
Vomiting	6/17 (35.3%)	7
General disorders
Fatigue	11/17 (64.7%)	25
Fever	1/17 (5.9%)	1
General symptom	7/17 (41.2%)	7
Oedema NOS	2/17 (11.8%)	2
Pain	2/17 (11.8%)	4
Infections and infestations
Infection NOS	2/17 (11.8%)	2
Investigations
Alanine aminotransferase increased	2/17 (11.8%)	4
Alkaline phosphatase increased	2/17 (11.8%)	3
Aspartate aminotransferase increased	4/17 (23.5%)	7
Creatinine increased	4/17 (23.5%)	5
Hyperbilirubinemia	2/17 (11.8%)	2
Hypercholesterolemia	5/17 (29.4%)	16
Leukopenia	3/17 (17.6%)	11
Lymphopenia	3/17 (17.6%)	13
Neutrophil count decreased	1/17 (5.9%)	1
Platelet count decreased	1/17 (5.9%)	1
Weight loss	1/17 (5.9%)	1
Metabolism and nutrition disorders
Anorexia	3/17 (17.6%)	4
Blood bicarbonate decreased	1/17 (5.9%)	1
Dehydration	1/17 (5.9%)	1
Hyperglycemia	15/17 (88.2%)	31
Hyperkalemia	1/17 (5.9%)	1
Hypermagnesemia	1/17 (5.9%)	1
Hypertriglyceridemia	1/17 (5.9%)	1
Hyperuricemia	1/17 (5.9%)	1
Hypoalbuminemia	8/17 (47.1%)	11
Hypocalcemia	4/17 (23.5%)	6
Hypokalemia	3/17 (17.6%)	3
Hypomagnesemia	3/17 (17.6%)	3
Hyponatremia	6/17 (35.3%)	6
Hypophosphatemia	1/17 (5.9%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal disorder	1/17 (5.9%)	2
Myalgia	1/17 (5.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	2/17 (11.8%)	3
Nervous system disorders
Depressed level of consciousness	2/17 (11.8%)	2
Dizziness	2/17 (11.8%)	2
Headache	5/17 (29.4%)	5
Neurological disorder NOS	1/17 (5.9%)	1
Peripheral sensory neuropathy	2/17 (11.8%)	5
Psychiatric disorders
Anxiety	1/17 (5.9%)	1
Confusion	1/17 (5.9%)	1
Insomnia	1/17 (5.9%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/17 (5.9%)	1
Cough	3/17 (17.6%)	4
Dyspnea	3/17 (17.6%)	3
Pleuritic pain	1/17 (5.9%)	2
Respiratory disorder	1/17 (5.9%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/17 (5.9%)	11
Erythema multiforme	1/17 (5.9%)	1
Rash desquamating	3/17 (17.6%)	3
Skin discolouration	1/17 (5.9%)	1
Vascular disorders
Hypertension	1/17 (5.9%)	2
Hypotension	2/17 (11.8%)	2

Limitations/Caveats

Study was terminated early after the first stage of a two-stage design, allowing for early termination for discouraging results

More Information

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.