ClinicalTrials.gov processed this data on March 28, 2024Link to the current ClinicalTrials.gov record.https://clinicaltrials.gov/ct2/show/NCT00031681NCI-2009-00019NCI-2009-00019NCI-5582WUSM-SCC-0102CDR0000069215UVACC-SCC-0102SCC 01-025582P30CA044579NCT000316817-Hydroxystaurosporine and Irinotecan Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors or Triple Negative Breast Cancer (Currently Accruing Only Triple-negative Breast Cancer Patients Since 6/8/2007)A Phase I Study of UCN-01 in Combination With Irinotecan in Resistant Solid Tumor Malignancies (Part I) and in Triple Negative (ER-Negative, PgR-Negative, HER-2 Not-Amplified) Recurrent Breast Cancers (Part II)National Cancer Institute (NCI)NIHWashington University Siteman Cancer CenterOther
This phase I trial is studying the side effects and best dose of giving
7-hydroxystaurosporine together with irinotecan hydrochloride in treating patients with
metastatic or unresectable solid tumors, including triple-negative breast cancer (currently
enrolling only patients with triple-negative breast cancer since 6/8/2007). Drugs used in
chemotherapy use different ways to stop tumor cells from dividing so they stop growing or
die. Giving 7-hydroxystaurosporine together with irinotecan hydrochloride may help kill more
cancer cells by making tumor cells more sensitive to the drug.
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose of UCN-01 (7-hydroxystaurosporine) and irinotecan
(irinotecan hydrochloride) in patients with resistant solid tumors. (Part I [closed to
accrual as of 6/8/2007]) II. Determine the dose-limiting toxicity of this regimen in these
patients. (Part I [closed to accrual as of 6/8/2007]) III. Determine the types of toxic
effects of this regimen in these patients. (Part I [closed to accrual as of 6/8/2007]) IV.
Determine the anti-tumor activity in terms of overall response rate (partial response [PR]
and complete response [CR]), clinical benefit rate (PR, CR, and stable disease), and time to
disease progression in patients with estrogen receptor-negative, progesterone
receptor-negative, and HER-2 not amplified (triple negative) locally recurrent or metastatic
breast cancer treated with this regimen. (Part II) V. Determine the side effect profile of
this regimen in patients with triple negative recurrent breast cancer. (Part II)
SECONDARY OBJECTIVES:
I. Determine any anti-tumor activity of this regimen in these patients. (Part I [closed to
accrual as of 6/8/2007]) II. Determine the pharmacokinetics of this regimen in these
patients. (Part I [closed to accrual as of 6/8/2007]) III. Determine the activity of the
serum α-acid glycoprotein and correlate this level with free UCN-01 concentrations. (Part I
[closed to accrual as of 6/8/2007]) IV. Determine the in vivo mechanisms of UCN-01 activity
in these patients.
OUTLINE: This is a dose-escalation study.
PART I: Patients receive irinotecan hydrochloride intravenously (IV) over 90 minutes on days
1, 8, 15, and 22 and 7-hydroxystaurosporine IV over 3 hours on days 2 and 23. Courses repeat
every 42 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6
patients receive escalating doses of irinotecan hydrochloride and 7-hydroxystaurosporine
until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose
preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Blood
samples are collected periodically during study treatment.
PART II: (treatment of triple negative recurrent breast cancer): Patients receive irinotecan
hydrochloride IV and 7-hydroxystaurosporine IV as in part I at the MTD and undergo blood
sample collection.
CompletedDecember 2001January 2011Phase 1InterventionalNoN/ASingle Group AssignmentTreatmentNone (Open Label)MTD of irinotecan hydrochloride in combination with 7-hydroxystaurosporine in patients with resistant solid tumor malignancies (Part I)Part IDefined as the highest dose given to at least 6 patients in which =< 1 out of 6 experience dose limiting toxicity (DLT).DLT of irinotecan hydrochloride in combination with 7-hydroxystaurosporine in patients with resistant solid tumor malignancies (Part I)Part IToxicities associated with irinotecan hydrochloride in combination with 7-hydroxystaurosporine in patients with resistant solid tumor malignancies (Part I)Continuously over study treatmentGraded using the Cancer Therapy Evaluation Program (CTEP) Active Version of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).Anti-tumor activity of 7-hydroxystaurosporine in combination with irinotecan hydrochloride in ER-negative, PgR-negative, HER-2 not-amplified (triple negative) recurrent breast cancer (Part II)Every 6 weeksIncluding overall response rate (partial response [PR] +complete response [CR]), clinical benefit rate (PR+CR+stable disease [SD]), and time to disease progression. 95% confidence interval will be calculated. Evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.Side effect profile of 7-hydroxystaurosporine in combination with irinotecan hydrochloride in triple negative recurrent breast cancer (Part II)Continuously over study treatment95 % confidence interval will be calculated.Anti-tumor activity of the combination of irinotecan hydrochloride and 7-hydroxystaurosporine in treatment of patients with resistant solid tumor malignanciesEvery 6 weeksEvaluated by the RECIST criteria.Pharmacokinetics of irinotecan hydrochloride and 7-hydroxystaurosporine when administered in combinationWeekly during the first 4 weeks of course 1Using the high-performance liquid chromatography (HPLC) assays.Serum alpha-acid glycoprotein and correlate this level with free 7-hydroxystaurosporine concentrationsWeekly during the first 4 weeks of course 1In vivo mechanistic basis for 7-hydroxystaurosporine activityWeekly during the first 4 weeks of course 1Explored by subgroup analysis (responders versus non-responders) on pharmacodynamic measures.141Advanced Adult Primary Liver CancerCarcinoma of the AppendixEstrogen Receptor-negative Breast CancerExtensive Stage Small Cell Lung CancerGastrointestinal Stromal TumorHER2-negative Breast CancerMetastatic Gastrointestinal Carcinoid TumorOvarian SarcomaOvarian Stromal CancerProgesterone Receptor-negative Breast CancerRecurrent Adenoid Cystic Carcinoma of the Oral CavityRecurrent Adult Primary Liver CancerRecurrent Anal CancerRecurrent Basal Cell Carcinoma of the LipRecurrent Borderline Ovarian Surface Epithelial-stromal TumorRecurrent Breast CancerRecurrent Cervical CancerRecurrent Colon CancerRecurrent Endometrial CarcinomaRecurrent Esophageal CancerRecurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal CavityRecurrent Extrahepatic Bile Duct CancerRecurrent Gallbladder CancerRecurrent Gastric CancerRecurrent Gastrointestinal Carcinoid TumorRecurrent Inverted Papilloma of the Paranasal Sinus and Nasal CavityRecurrent Lymphoepithelioma of the NasopharynxRecurrent Lymphoepithelioma of the OropharynxRecurrent Metastatic Squamous Neck Cancer With Occult PrimaryRecurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal CavityRecurrent Mucoepidermoid Carcinoma of the Oral CavityRecurrent Non-small Cell Lung CancerRecurrent Ovarian Epithelial CancerRecurrent Ovarian Germ Cell TumorRecurrent Pancreatic CancerRecurrent Prostate CancerRecurrent Rectal CancerRecurrent Salivary Gland CancerRecurrent Small Cell Lung CancerRecurrent Small Intestine CancerRecurrent Squamous Cell Carcinoma of the HypopharynxRecurrent Squamous Cell Carcinoma of the LarynxRecurrent Squamous Cell Carcinoma of the Lip and Oral CavityRecurrent Squamous Cell Carcinoma of the NasopharynxRecurrent Squamous Cell Carcinoma of the OropharynxRecurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal CavityRecurrent Verrucous Carcinoma of the LarynxRecurrent Verrucous Carcinoma of the Oral CavitySmall Intestine AdenocarcinomaSmall Intestine LeiomyosarcomaSmall Intestine LymphomaStage IV Adenoid Cystic Carcinoma of the Oral CavityStage IV Anal CancerStage IV Basal Cell Carcinoma of the LipStage IV Borderline Ovarian Surface Epithelial-stromal TumorStage IV Breast CancerStage IV Colon CancerStage IV Endometrial CarcinomaStage IV Esophageal CancerStage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal CavityStage IV Gastric CancerStage IV Inverted Papilloma of the Paranasal Sinus and Nasal CavityStage IV Lymphoepithelioma of the NasopharynxStage IV Lymphoepithelioma of the OropharynxStage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal CavityStage IV Mucoepidermoid Carcinoma of the Oral CavityStage IV Non-small Cell Lung CancerStage IV Ovarian Epithelial CancerStage IV Ovarian Germ Cell TumorStage IV Pancreatic CancerStage IV Prostate CancerStage IV Rectal CancerStage IV Salivary Gland CancerStage IV Squamous Cell Carcinoma of the HypopharynxStage IV Squamous Cell Carcinoma of the LarynxStage IV Squamous Cell Carcinoma of the Lip and Oral CavityStage IV Squamous Cell Carcinoma of the NasopharynxStage IV Squamous Cell Carcinoma of the OropharynxStage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal CavityStage IV Verrucous Carcinoma of the LarynxStage IV Verrucous Carcinoma of the Oral CavityStage IVA Cervical CancerStage IVB Cervical CancerTriple-negative Breast CancerUnresectable Extrahepatic Bile Duct CancerUnresectable Gallbladder CancerUnspecified Adult Solid Tumor, Protocol SpecificUntreated Metastatic Squamous Neck Cancer With Occult PrimaryTreatment (combination chemotherapy)ExperimentalPART I: Patients receive irinotecan hydrochloride IV over 90 minutes on days 1, 8, 15, and 22 and 7-hydroxystaurosporine IV over 3 hours on days 2 and 23. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of irinotecan hydrochloride and 7-hydroxystaurosporine until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Blood samples are collected periodically during study treatment.
PART II: (treatment of triple negative recurrent breast cancer): Patients receive irinotecan hydrochloride IV and 7-hydroxystaurosporine IV as in part I at the MTD and undergo blood sample collection.Drug7-hydroxystaurosporineGiven IVTreatment (combination chemotherapy)UCN-01Drugirinotecan hydrochlorideGiven IVTreatment (combination chemotherapy)CamptoCamptosarCPT-11irinotecanU-101440EOtherdiagnostic laboratory biomarker analysisCorrelative studiesTreatment (combination chemotherapy)
Inclusion Criteria:
- Part I (closed to accrual as of 6/8/2007)
- Histologically confirmed solid tumor that is metastatic or unresectable for which
standard curative measures do not exist or are no longer effective, including the
following:
- Gastrointestinal tract cancer
- Lung cancer
- Breast cancer
- Ovarian cancer
- Endometrial cancer
- Cervical cancer
- Prostate cancer
- Head and neck cancer
- Patients with or without measurable or evaluable disease allowed
- Measurable disease, defined as ≥ 1 unidimensionally measurable lesion > 20
mm by conventional techniques or ≥ 10 mm with spiral CT scan
- Tumor markers allowed for evaluable disease
- Positive bone scan, osteoblastic metastases, and pleural or peritoneal
effusions are not considered measurable or evaluable disease
- No known brain metastases
- Part II
- Histologically confirmed (either primary or the recurrent site) locally recurrent
or metastatic breast cancer not amendable to surgery
- Measurable disease
- For skin lesions, documentation by color photography and estimation of
lesion size with a ruler are required
- Must have undergone prior therapy with an anthracycline and a taxane either in
the adjuvant or metastatic setting
- CNS metastasis allowed provided stable disease (i.e., no evidence of local
progression) ≥ 3 months after local therapy
- Hormone receptor status:
- Estrogen receptor negative
- Progesterone receptor negative
- HER-2 not amplified by fluorescence in situ hybridization
- Performance status - ECOG 0-2
- Performance status - Karnofsky 60-100%
- More than 12 weeks
- WBC at least 3,000/mm^3
- Absolute neutrophil count at least 1,500/mm^3
- Platelet count at least 100,000/mm^3
- Hemoglobin ≥ 10 g/dL
- Bilirubin normal
- AST/ALT no greater than 3 times upper limit of normal (ULN)
- No Gilbert's disease
- No chronic unconjugated hyperbilirubinemia
- Creatinine no greater than 1.5 times ULN
- Creatinine clearance at least 60 mL/min
- No symptomatic cardiac dysfunction
- No symptomatic pulmonary dysfunction
- Oxygen saturation at least 90% by pulse oximetry on room air at rest and after walking
6 minutes
- No insulin-dependent diabetes mellitus
- No other uncontrolled concurrent illness
- No active or ongoing infection
- No psychiatric illness or social situation that would preclude study entry
- No prior allergic reactions attributed to compounds of similar chemical or biological
composition to UCN-01 or irinotecan
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- No concurrent granulocyte colony-stimulating factors (filgrastim [G-CSF] or
sargramostim [GM-CSF]) during the first course of study
- See Disease Characteristics (Part II)
- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and
recovered
- Prior irinotecan allowed
- Less than 4 prior chemotherapy regimens in the adjuvant and/or metastatic setting
(Part II)
- More than 4 weeks since prior radiotherapy and recovered
- Concurrent warfarin allowed
- Concurrent subcutaneous heparin allowed
- No other concurrent investigational agents
- No concurrent anticonvulsants (e.g., carbamazepine, phenobarbital, or phenytoin)
- No concurrent combination antiretroviral therapy for HIV-positive patients
All18 YearsN/ANoPaula FracassoPrincipal InvestigatorUniversity of VirginiaUniversity of VirginiaCharlottesvilleVirginia22908United StatesUnited StatesSeptember 2013March 8, 2002January 26, 2003January 27, 2003September 27, 2013September 27, 2013September 30, 2013SponsorCarcinomaNeoplasmsBreast NeoplasmsLung NeoplasmsProstatic NeoplasmsCarcinoma, Non-Small-Cell LungCarcinoma, Squamous CellPancreatic NeoplasmsStomach NeoplasmsRectal NeoplasmsHead and Neck NeoplasmsUterine Cervical NeoplasmsColonic NeoplasmsEsophageal NeoplasmsSmall Cell Lung CarcinomaLiver NeoplasmsTriple Negative Breast NeoplasmsNeoplasms, Germ Cell and EmbryonalCarcinoma, Ovarian EpithelialLaryngeal NeoplasmsCarcinoma, Basal CellOropharyngeal NeoplasmsCarcinoma, VerrucousGastrointestinal Stromal TumorsSquamous Cell Carcinoma of Head and NeckPapillomaEndometrial NeoplasmsSalivary Gland NeoplasmsCarcinoid TumorNasopharyngeal CarcinomaAnus NeoplasmsParanasal Sinus NeoplasmsGallbladder NeoplasmsGerminomaOvarian NeoplasmsCarcinoma, Adenoid CysticLeiomyosarcomaBile Duct NeoplasmsCholangiocarcinomaNeoplasms, Unknown PrimaryCarcinoma, MucoepidermoidMucoepidermoid TumorEsthesioneuroblastoma, OlfactoryPapilloma, InvertedMalignant Carcinoid SyndromeGastrointestinal NeoplasmsIntestinal NeoplasmsBrenner TumorLaryngeal DiseasesGranulomaRecurrenceIrinotecan7-hydroxystaurosporine