Small Cell CarcinomaPhase 1NCT00466232
Phase I Study of Weekly Topotecan in Combination With Sorafenib in Treatment of Relapsed Small Cell Lung Cancer
A Phase 1 study testing Topotecan and Sorafenib in people with Small Cell Carcinoma and Lung Cancer, run by HealthPartners Institute at 1 site in United States.
Trial summary
The primary objective of this study is to determine the maximum tolerated dose of sorafenib up to the full active dose when combined with standard weekly dosing of topotecan in patients with recurrent small cell lung cancer and to characterize the toxicities associated with the combination of topotecan and sorafenib… Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Small Cell Carcinoma, Lung Cancer
- What is being tested?
- Topotecan and Sorafenib
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 16 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2007to Mar 2010
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Patients must have histologically proven small cell carcinoma of bronchogenic origin.
- Must have received one course of systemic chemotherapy which included cisplatin or carboplatin. Chemotherapy administered during radiation is allowable.
- Must have radiographically documented disease recurrence or progression by CT scan or bone scan. CNS only recurrence is not sufficient. Measurable disease per RECIST criteria is not required.
- ECOG Performance status of 0 to 2
- Adequate organ function within 14 days of study enrollment as defined by the following:
- Absolute neutrophil count ≥ 1500/mm3
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- Platelet count ≥ 100,000/mm3
- Hemoglobin ≥ 9 gm/dL
- Creatinine ≤ 1.5 mg/dL
- Bilirubin < 1.5 times upper limit of normal (x UNL)
- Alkaline phosphatase, aspartate transaminase and alanine transaminase < 3 x ULN (may be <5 x ULN if hepatic metastases)
- Women of childbearing potential and sexually active males must use an effective method of contraception during the study and for 3 months after the last dose of study drug.
- Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment.
- Treated brain metastases that are stable for a minimum of 4 weeks following surgery or radiation and off therapeutic glucocorticoids are allowed.
- INR<1.5 or a PT/PTT within normal limits. Patients receiving anti- coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable.
- Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.
Who cannot join
- Pregnant or breast feeding.
- Myocardial infarction or cerebrovascular accident within 6 months.
- Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg despite optimal medical management.
- History of other active invasive malignancy (except for basal cell or squamous cell skin cancer) within 12 months.
- Major surgery within 4 weeks.
- Chemotherapy within 4 weeks.
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- Cardiac disease: Congestive heart failure > NYHA Class II, unstable or new-onset angina within prior 3 months.
- History of bleeding diathesis or coagulopathy.
- Active clinically serious infection > CTCAE Grade 2.
- Ventricular arrhythmias requiring anti-arrhythmic therapy.
- Serious non-healing wound, ulcer or fracture.
- Any hemorrhage or bleeding event > CTCAE Grade 3 within 4 weeks of study enrollment.
- Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first dose of study drug.
- Thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
- Known human immunodeficiency virus (HIV) or chronic hepatitis B or C infection.
- Any condition that impairs patient's ability to swallow whole pills.
- Any gastrointestinal malabsorption syndrome
- Use of St. John's wort or rifampin.
Trial locations and contacts
1 site in 1 country.
United States1 site
Park Nicollet Institute
Saint Louis Park, Minnesota, 55416
About this study
The primary objective of this study is to determine the maximum tolerated dose of sorafenib up to the full active dose when combined with standard weekly dosing of topotecan in patients with recurrent small cell lung cancer and to characterize the toxicities associated with the combination of topotecan and sorafenib in this patient population
Read the detailed description
Small cell lung cancer (SCLC) comprises approximately 15 percent of all lung cancers in the United States. It is highly correlated with tobacco use and occurs almost exclusively in smokers. SCLC is a particularly virulent malignancy characterized by rapid growth and a tendency to metastasize early in the disease course. In first line treatment, SCLC has a high response rate to cytotoxic chemotherapy. Unfortunately, the disease develops drug resistance in almost all cases resulting in recurrence. In second line treatment, the likelihood of response to treatment is considerably less. Multiple agents have been used in this setting with response rates typically around 25% and median survival of less than 6 months1-3. There is clearly a great need for more effective treatments in this disease.
Topotecan is a semi-synthetic, water soluble derivative of camptothecin, a cytotoxic alkaloid extracted from plants of the genus Camptotheca. Its mechanism of action is inhibition of topoisomerase I, an enzyme necessary to relieve torsional strain of DNA which is necessary to carry out replication. This results in DNA double-strand breaks and ultimately cell death. Topotecan has demonstrated activity in a number of malignancies and is currently indicated for the treatment of ovarian cancer, cervical cancer and recurrent small cell lung cancer.
Topotecan has demonstrated single agent activity in recurrent small cell lung cancer in a number of trials. Reported response rates range from 2 to 31%3-7. A phase III trial compared topotecan to CAV (cyclophosphamide, doxorubicin and vincristine) in treatment of recurrent SCLC5. Response rate, survival and time to progression were similar in both groups. The topotecan group demonstrated significant improvement in symptoms including anorexia, fatigue and dyspnea. This led to FDA approval of topotecan for treatment of recurrent SCLC.
The dose limiting toxicity of topotecan is hematologic. The approved schedule of administration is 1.5mg/m2 daily x 5 every 21 days. A modified schedule of weekly administration at 4mg/m2 has been shown to have similar efficacy with less toxicity8 and has been widely adopted in clinical practice.
Sorafenib is an oral multi-kinase inhibitor with effects on tumor proliferation and tumor angiogenesis. It has several biochemically important mechanisms including inhibition of Raf-1 and B-Raf which are pivotal components of the Ras/Raf/Mek/Erk signaling pathway. It also has inhibitory activity against the tyrosine kinases for VEGF and PDGFR as well as Flt-3 and c-kit.
Sorafenib has been safely combined with full dose cytotoxic chemotherapy in several Phase I trials9-11. There is no data on the combination of topotecan and sorafenib to date. Sorafenib is metabolized in the liver undergoing oxidation via CYP3A4 and glucuronidation via UGT1A9. There is no evidence that topotecan affects activity of the cytochrome P450 pathways suggesting low likelihood of a drug-drug interaction. There are no significant overlapping toxicities making this an ideal drug combination to investigate.
- Conditions
- Small Cell Carcinoma, Lung Cancer
- Keywords
- Small Cell, Lung Cancer, Treatment
- Medical subject headings
- Carcinoma, Small Cell, Lung Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TopotecanDrug
Also called Hycamtin
4 mg/m2 IV on day 1, 8, 15. Repeat every 28 days.
SorafenibDrug
Also called Nexavar
Dose escalation study at 3 dose levels: 200 mg po daily, 200 mg po bid, 400 mg po bid.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | Weekly Topetecan in combination with Sorafenib Receives: Drug: Topotecan; Drug: Sorafenib |
What is being measured
The primary outcome is the main question the study is designed to answer.
The primary objective of this study is to determine the maximum tolerated dose of sorafenib up to the full active dose when combined with standard weekly dosing of topotecan in patients with recurrent small cell lung cancer and to
Measured: 2 years
characterize the toxicities associated with the combination of topotecan and sorafenib in this patient population
Measured: 2 years
Secondary outcomes (4)
To evaluate the objective response rate (CR, PR or stable disease)
Measured: 2 years
To measure time-to-event efficacy looking at the following variables:
Measured: 2 years
o Time to disease progression
Measured: 2 years
o Overall survival
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Apr 2007 (estimated)
- Study startApr 2007
- Primary completionDec 2009
- Study completionMar 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Small Cell CarcinomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 16 participants (actual)
Sponsor and investigators
- Lead sponsor
- HealthPartners Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Joseph Leach, MD, Principal investigator, HealthPartners Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00466232
- Sponsor's protocol ID
- 3557-07-C
- Status last verified
- Apr 2007
- First submitted
- 24 Apr 2007
- Last updated
- 16 Dec 2015
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 16 Dec 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Study of Weekly Topotecan in Combination With Sorafenib in Treatment of Relapsed Small Cell Lung Cancer
- ClinicalTrials.gov ID
- NCT00466232
- Acronym / sponsor ID
- 3557-07-C
- Conditions
- Small Cell Carcinoma, Lung Cancer
- Keywords
- Small Cell, Lung Cancer, Treatment
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 16 participants (actual)
- Lead sponsor
- HealthPartners InstituteUniversity, hospital or other
- Study start
- Apr 2007
- Primary completion
- Dec 2009 (actual)
- Study completion
- Mar 2010 (actual)
- First posted
- 27 Apr 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary objective of this study is to determine the maximum tolerated dose of sorafenib up to the full active dose when combined with standard weekly dosing of topotecan in patients with recurrent small cell lung cancer and to characterize the toxicities associated with the combination of topotecan and sorafenib in this patient population
Detailed description
Small cell lung cancer (SCLC) comprises approximately 15 percent of all lung cancers in the United States. It is highly correlated with tobacco use and occurs almost exclusively in smokers. SCLC is a particularly virulent malignancy characterized by rapid growth and a tendency to metastasize early in the disease course. In first line treatment, SCLC has a high response rate to cytotoxic chemotherapy. Unfortunately, the disease develops drug resistance in almost all cases resulting in recurrence. In second line treatment, the likelihood of response to treatment is considerably less. Multiple agents have been used in this setting with response rates typically around 25% and median survival of less than 6 months1-3. There is clearly a great need for more effective treatments in this disease.
Topotecan is a semi-synthetic, water soluble derivative of camptothecin, a cytotoxic alkaloid extracted from plants of the genus Camptotheca. Its mechanism of action is inhibition of topoisomerase I, an enzyme necessary to relieve torsional strain of DNA which is necessary to carry out replication. This results in DNA double-strand breaks and ultimately cell death. Topotecan has demonstrated activity in a number of malignancies and is currently indicated for the treatment of ovarian cancer, cervical cancer and recurrent small cell lung cancer.
Topotecan has demonstrated single agent activity in recurrent small cell lung cancer in a number of trials. Reported response rates range from 2 to 31%3-7. A phase III trial compared topotecan to CAV (cyclophosphamide, doxorubicin and vincristine) in treatment of recurrent SCLC5. Response rate, survival and time to progression were similar in both groups. The topotecan group demonstrated significant improvement in symptoms including anorexia, fatigue and dyspnea. This led to FDA approval of topotecan for treatment of recurrent SCLC.
The dose limiting toxicity of topotecan is hematologic. The approved schedule of administration is 1.5mg/m2 daily x 5 every 21 days. A modified schedule of weekly administration at 4mg/m2 has been shown to have similar efficacy with less toxicity8 and has been widely adopted in clinical practice.
Sorafenib is an oral multi-kinase inhibitor with effects on tumor proliferation and tumor angiogenesis. It has several biochemically important mechanisms including inhibition of Raf-1 and B-Raf which are pivotal components of the Ras/Raf/Mek/Erk signaling pathway. It also has inhibitory activity against the tyrosine kinases for VEGF and PDGFR as well as Flt-3 and c-kit.
Sorafenib has been safely combined with full dose cytotoxic chemotherapy in several Phase I trials9-11. There is no data on the combination of topotecan and sorafenib to date. Sorafenib is metabolized in the liver undergoing oxidation via CYP3A4 and glucuronidation via UGT1A9. There is no evidence that topotecan affects activity of the cytochrome P450 pathways suggesting low likelihood of a drug-drug interaction. There are no significant overlapping toxicities making this an ideal drug combination to investigate.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: Topotecan, Drug: SorafenibWeekly Topetecan in combination with Sorafenib |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (16 listed)
- Patients must have histologically proven small cell carcinoma of bronchogenic origin.
- Must have received one course of systemic chemotherapy which included cisplatin or carboplatin. Chemotherapy administered during radiation is allowable.
- Must have radiographically documented disease recurrence or progression by CT scan or bone scan. CNS only recurrence is not sufficient. Measurable disease per RECIST criteria is not required.
- ECOG Performance status of 0 to 2
- Adequate organ function within 14 days of study enrollment as defined by the following:
Key exclusion criteria (18 listed)
- Pregnant or breast feeding.
- Myocardial infarction or cerebrovascular accident within 6 months.
- Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg despite optimal medical management.
- History of other active invasive malignancy (except for basal cell or squamous cell skin cancer) within 12 months.
- Major surgery within 4 weeks.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TopotecanAlso: Hycamtin4 mg/m2 IV on day 1, 8, 15. Repeat every 28 days. | Drug | 1 |
| SorafenibAlso: NexavarDose escalation study at 3 dose levels: 200 mg po daily, 200 mg po bid, 400 mg po bid. | Drug | 1 |
Primary outcome
The primary objective of this study is to determine the maximum tolerated dose of sorafenib up to the full active dose when combined with standard weekly dosing of topotecan in patients with recurrent small cell lung cancer and to
Time frame: 2 years
characterize the toxicities associated with the combination of topotecan and sorafenib in this patient population
Time frame: 2 years
4 secondary outcomes
To evaluate the objective response rate (CR, PR or stable disease)
Time frame: 2 years
To measure time-to-event efficacy looking at the following variables:
Time frame: 2 years
o Time to disease progression
Time frame: 2 years
o Overall survival
Time frame: 2 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Dec 2015.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Joseph Leach, MD principal investigator
HealthPartners Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Topotecan and Sorafenib in people with Small Cell Carcinoma and Lung Cancer, run by HealthPartners Institute at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Dec 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The primary objective of this study is to determine the maximum tolerated dose of sorafenib up to the full active dose when combined with standard weekly dosing of topotecan in patients with recurrent small cell lung cancer and to (time frame: 2 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Dec 2015.