Solid TumorsPhase 1NCT00553189
Safety Study of ABT-888 Plus Topotecan Hydrochloride to Treat Patients With Solid Tumors and Lymphomas
A Phase 1 study testing ABT-888 and Topotecan in people with Solid Tumors and Lymphomas, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
Background: PARP is an enzyme that is involved in the repair of damage to DNA. Levels of the enzyme are higher in tumor cells than in normal cells, and may play a part in resistance to cancer chemotherapy and radiation therapy. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Solid Tumors, Lymphomas
- What is being tested?
- ABT-888 and Topotecan
- How many people
- 31 participants
- Where
- 1 siteUnited States
- Study dates
- 9 Aug 2007to 28 Sep 2011
- 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
None listed.
Who cannot join
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Patients must be greater than or equal to 2 weeks since any investigational agent administered as part of a Phase 0 study, and should have recovered to eligibility levels from any toxicities.
- Patients who have been administered ABT-888 as part of a single or limited dosing study, such as a Phase 0 study, should not be excluded from participating in this study solely because of receiving prior ABT-888.
- Patients who have received prior TPT should not be excluded solely because of receiving prior TPT.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, prolonged QTc interval (greater than msec), or psychiatric illness/social situations that would limit compliance with study requirements.
- Patients with known brain mestastases or a history of seizures are excluded from this clinical trial.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: A Phase I Study of ABT-888 in Combination With Topotecan Hydrochloride in Adults With Refractory Solid Tumors and Lymphomas
Background:
- PARP is an enzyme that is involved in the repair of damage to DNA. Levels of the enzyme are higher in tumor cells than in normal cells, and may play a part in resistance to cancer chemotherapy and radiation therapy. ABT-888 is an experimental drug that inhibits PARP and may help to increase the effectiveness of cancer treatments designed to damage DNA in cancer cells.
- Topotecan is a drug approved by the Food and Drug Administration for treating certain cancers.
- This dose escalation study will test the two drugs at successively higher doses in small groups of patients until the highest safe dose is determined.
Read more
Objectives:
- To test the safety of the combination of ABT-888 and Topotecan (TPT) and determine the highest dose of each drug that can be safely given to humans. This is the maximum tolerated dose (MTD).
- To learn how the combination of ABT-888 and TPT works in humans and how the body handles the drugs.
- To determine the side effects of the combination of ABT-888 and TPT at the tested doses.
Eligibility:
-Patients with solid tumors, lymphomas and chronic lymphocytic leukemia whose disease has progressed following standard therapy or for whom standard treatments are not available.
Design:
- ABT-888 and TPT are given in 21-day treatment cycles. At the start of the study, TPT is infused through a vein over 30 minutes about a week before cycle 1 starts. Starting on day 1 of cycle 1, ABT-888 is given by mouth twice a day for 7 days. TPT is given through a vein daily for 4 days starting on day 2. After the last dose of ABT-888 day 7, no more treatment is given for the rest of the 21-day cycle.
- For the remaining cycles, ABT-888 is given twice a day by mouth on days 1 to 7 of each cycle, and TPT is given through a vein daily on days 1 to 5 of each cycle.
- The first three to six patients enrolled in the study take the smallest study dose of the drugs. If they do not develop significant adverse side effects, successive small groups of patients take the drug at increasingly higher doses until the MTD is reached. Additional patients enrolled receive the MTD.
- Patients have periodic clinic visits for their TPT infusions and for tests and examinations. Evaluations include measurement of vital signs, physical examinations, blood and urine tests, electrocardiograms and CT or other imaging tests, such as ultrasound or MRI. Tumor biopsies may be requested to study the effects of the drugs on the...
Read the detailed description
Background:
- The PARP family of enzymes is characterized by the ability to poly (ADP-ribosyl)ate protein substrates. PARP-1 and PARP-2 play a critical role in the maintenance of genomic stability by regulating a variety of DNA repair mechanisms.
- Poly (ADP-ribosylated) PARP-1 has been shown to block the formation of topo 1-DNA cleavage and accelerate the removal of camptothecin-stabilized topo 1-DNA complexes. PARP-1 inhibition may therefore prevent efficient repair of DNA damage induced by topoisomerase 1 inhibitors. ABT-888 is an oral PARP inhibitor and topotecan is a topoisomerase I inhibitor.
Objectives:
- Establish the safety and tolerability of the combination of ABT-888 with topotecan hydrochloride in patients with refractory solid tumors and lymphomas.
- Establish the maximum tolerated dose of the combination of ABT-888 with topotecan hydrochloride.
- Evaluate the pharmacokinetics of each agent alone and in combination.
- Determine the effects of the study treatment on the level of PARP inhibition and DNA damage in PBMCs and tumor samples.
Eligibility:
- Patients with histologically documented solid tumors and lymphoid malignancies (lymphoma and CLL) whose disease has progressed following standard therapy or who have no acceptable standard treatment options.
- No major surgery, radiation or chemotherapy within four weeks prior to study enrollment, and recovered from toxicities of prior therapies to at least eligibility levels.
Study Design:
- Cycle 1, dose levels -1 to 7 and 1B: Topotecan (TPT) will be administered intravenously over 30 minutes as a single dose on days 1-5. Starting on day 2, ABT-888 will be administered orally twice a day on a q12 hour schedule for 4 days (D2-5). Following the completion of study drug administration on day 5, no further treatment will be administered for the rest of this 21-day cycle. Growth factors will be administered prophylactically starting Cycle 1 to patients on dose level 1B only.
- Cycle 2 and beyond, dose levels -1 to 7 and 1B: ABT-888 will be administered twice a day on a q12 hour schedule orally on days 1-5. TPT will be given IV daily from days 1-5, in a 21-day cycle. Growth factors will be administered prophylactically to patients on dose level 1B only.
- All cycles, dose levels -2 and 1A to 5A: ABT-888 will be administered on day 1 only for dose levels -2 and 1A, 2A, 3A, and 4A. For dose level 5A, ABT-888 will be administered on days 1 and 2 of each cycle. TPT will be given IV daily from days 1-5, in a 21-day cycle.
- Dose escalation will proceed as outlined below. Once maximum tolerated dose (MTD) is established, 6 additional patients will be enrolled at the MTD to further define the dose and evaluate PD studies at this dose level.
- Conditions
- Solid Tumors, Lymphomas
- Being tested
- ABT-888, Topotecan
- Keywords
- PARP Inhibitor, Advanced Cancer, Combination Therapy, Early Trial, DNA Damage Repair, Topotecan, Cancer, Solid Tumor, Lymphoma
- Medical subject headings
- Lymphoma, Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ABT-888Drug
TopotecanDrug
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety and tolerability of the combination of ABT-888 with topotecan hydrochloride in patients with refractory solid tumors and lymphomas; Establish the maximum tolerated dose of ABT-888 with topotecan hydrochloride.
Secondary outcomes (1)
Evaluate the pharmacokinetic of each agent alone and in combination; determine the effects of the study treatment on the level of PARP inhibition and DNA damage in PBMCs and tumor samples.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Nov 2007 (estimated)
- Study start9 Aug 2007
- Primary completion1 Feb 2008
- Study completion28 Sep 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Solid TumorsStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- 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
- Factorial
- Masking
- None (open label)
- Enrolment
- 31 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00553189
- Sponsor's protocol ID
- 070203
- Other IDs
- 07-C-0203
- Status last verified
- 28 Sep 2011
- First submitted
- 2 Nov 2007
- Last updated
- 2 Jul 2017
- Results posted
- No
Publications
Ame JC, Rolli V, Schreiber V, Niedergang C, Apiou F, Decker P, Muller S, Hoger T, Menissier-de Murcia J, de Murcia G. PARP-2, A novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase. J Biol Chem. 1999 Jun 18;274(25):17860-8. doi: 10.1074/jbc.274.25.17860.
PubMed 10364231Ame JC, Spenlehauer C, de Murcia G. The PARP superfamily. Bioessays. 2004 Aug;26(8):882-93. doi: 10.1002/bies.20085.
PubMed 15273990Berger NA, Adams JW, Sikorski GW, Petzold SJ, Shearer WT. Synthesis of DNA and poly(adenosine diphosphate ribose) in normal and chronic lymphocytic leukemia lymphocytes. J Clin Invest. 1978 Jul;62(1):111-8. doi: 10.1172/JCI109094.
PubMed 659624Kummar S, Chen A, Ji J, Zhang Y, Reid JM, Ames M, Jia L, Weil M, Speranza G, Murgo AJ, Kinders R, Wang L, Parchment RE, Carter J, Stotler H, Rubinstein L, Hollingshead M, Melillo G, Pommier Y, Bonner W, Tomaszewski JE, Doroshow JH. Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. Cancer Res. 2011 Sep 1;71(17):5626-34. doi: 10.1158/0008-5472.CAN-11-1227. Epub 2011 Jul 27.
PubMed 21795476
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Study of ABT-888 in Combination With Topotecan Hydrochloride in Adults With Refractory Solid Tumors and Lymphomas
- ClinicalTrials.gov ID
- NCT00553189
- Acronym / sponsor ID
- 070203
- Conditions
- Solid Tumors, Lymphomas
- Keywords
- PARP Inhibitor, Advanced Cancer, Combination Therapy, Early Trial, DNA Damage Repair, Topotecan, Cancer, Solid Tumor
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 31 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 9 Aug 2007
- Primary completion
- 1 Feb 2008 (actual)
- Study completion
- 28 Sep 2011 (actual)
- First posted
- 5 Nov 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.
Background:
- PARP is an enzyme that is involved in the repair of damage to DNA. Levels of the enzyme are higher in tumor cells than in normal cells, and may play a part in resistance to cancer chemotherapy and radiation therapy. ABT-888 is an experimental drug that inhibits PARP and may help to increase the effectiveness of cancer treatments designed to damage DNA in cancer cells.
- Topotecan is a drug approved by the Food and Drug Administration for treating certain cancers.
- This dose escalation study will test the two drugs at successively higher doses in small groups of patients until the highest safe dose is determined.
Objectives:
- To test the safety of the combination of ABT-888 and Topotecan (TPT) and determine the highest dose of each drug that can be safely given to humans. This is the maximum tolerated dose (MTD).
- To learn how the combination of ABT-888 and TPT works in humans and how the body handles the drugs.
- To determine the side effects of the combination of ABT-888 and TPT at the tested doses.
Eligibility:
-Patients with solid tumors, lymphomas and chronic lymphocytic leukemia whose disease has progressed following standard therapy or for whom standard treatments are not available.
Design:
- ABT-888 and TPT are given in 21-day treatment cycles. At the start of the study, TPT is infused through a vein over 30 minutes about a week before cycle 1 starts. Starting on day 1 of cycle 1, ABT-888 is given by mouth twice a day for 7 days. TPT is given through a vein daily for 4 days starting on day 2. After the last dose of ABT-888 day 7, no more treatment is given for the rest of the 21-day cycle.
- For the remaining cycles, ABT-888 is given twice a day by mouth on days 1 to 7 of each cycle, and TPT is given through a vein daily on days 1 to 5 of each cycle.
- The first three to six patients enrolled in the study take the smallest study dose of the drugs. If they do not develop significant adverse side effects, successive small groups of patients take the drug at increasingly higher doses until the MTD is reached. Additional patients enrolled receive the MTD.
- Patients have periodic clinic visits for their TPT infusions and for tests and examinations. Evaluations include measurement of vital signs, physical examinations, blood and urine tests, electrocardiograms and CT or other imaging tests, such as ultrasound or MRI. Tumor biopsies may be requested to study the effects of the drugs on the...
Detailed description
Background:
- The PARP family of enzymes is characterized by the ability to poly (ADP-ribosyl)ate protein substrates. PARP-1 and PARP-2 play a critical role in the maintenance of genomic stability by regulating a variety of DNA repair mechanisms.
- Poly (ADP-ribosylated) PARP-1 has been shown to block the formation of topo 1-DNA cleavage and accelerate the removal of camptothecin-stabilized topo 1-DNA complexes. PARP-1 inhibition may therefore prevent efficient repair of DNA damage induced by topoisomerase 1 inhibitors. ABT-888 is an oral PARP inhibitor and topotecan is a topoisomerase I inhibitor.
Objectives:
- Establish the safety and tolerability of the combination of ABT-888 with topotecan hydrochloride in patients with refractory solid tumors and lymphomas.
- Establish the maximum tolerated dose of the combination of ABT-888 with topotecan hydrochloride.
- Evaluate the pharmacokinetics of each agent alone and in combination.
- Determine the effects of the study treatment on the level of PARP inhibition and DNA damage in PBMCs and tumor samples.
Eligibility:
- Patients with histologically documented solid tumors and lymphoid malignancies (lymphoma and CLL) whose disease has progressed following standard therapy or who have no acceptable standard treatment options.
- No major surgery, radiation or chemotherapy within four weeks prior to study enrollment, and recovered from toxicities of prior therapies to at least eligibility levels.
Study Design:
- Cycle 1, dose levels -1 to 7 and 1B: Topotecan (TPT) will be administered intravenously over 30 minutes as a single dose on days 1-5. Starting on day 2, ABT-888 will be administered orally twice a day on a q12 hour schedule for 4 days (D2-5). Following the completion of study drug administration on day 5, no further treatment will be administered for the rest of this 21-day cycle. Growth factors will be administered prophylactically starting Cycle 1 to patients on dose level 1B only.
- Cycle 2 and beyond, dose levels -1 to 7 and 1B: ABT-888 will be administered twice a day on a q12 hour schedule orally on days 1-5. TPT will be given IV daily from days 1-5, in a 21-day cycle. Growth factors will be administered prophylactically to patients on dose level 1B only.
- All cycles, dose levels -2 and 1A to 5A: ABT-888 will be administered on day 1 only for dose levels -2 and 1A, 2A, 3A, and 4A. For dose level 5A, ABT-888 will be administered on days 1 and 2 of each cycle. TPT will be given IV daily from days 1-5, in a 21-day cycle.
- Dose escalation will proceed as outlined below. Once maximum tolerated dose (MTD) is established, 6 additional patients will be enrolled at the MTD to further define the dose and evaluate PD studies at this dose level.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Factorial
- Masking
- None (open label)
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (0 listed)
Key exclusion criteria (5 listed)
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Patients must be greater than or equal to 2 weeks since any investigational agent administered as part of a Phase 0 study, and should have recovered to eligibility levels from any toxicities.
- Patients who have been administered ABT-888 as part of a single or limited dosing study, such as a Phase 0 study, should not be excluded from participating in this study solely because of receiving prior ABT-888.
- Patients who have received prior TPT should not be excluded solely because of receiving prior TPT.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, prolonged QTc interval (greater than msec), or psychiatric illness/social situations that would limit compliance with study requirements.
- Patients with known brain mestastases or a history of seizures are excluded from this clinical trial.
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 |
|---|---|---|
| ABT-888 | Drug | – |
| Topotecan | Drug | – |
Primary outcome
Safety and tolerability of the combination of ABT-888 with topotecan hydrochloride in patients with refractory solid tumors and lymphomas; Establish the maximum tolerated dose of ABT-888 with topotecan hydrochloride.
1 secondary outcome
Evaluate the pharmacokinetic of each agent alone and in combination; determine the effects of the study treatment on the level of PARP inhibition and DNA damage in PBMCs and tumor samples.
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 2 Jul 2017.
- Background: PubMed 10364231Ame JC, Rolli V, Schreiber V, Niedergang C, Apiou F, Decker P, Muller S, Hoger T, Menissier-de Murcia J, de Murcia G. PARP-2, A novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase. J Biol Chem. 1999 Jun 18;274(25):17860-8. doi: 10.1074/jbc.274.25.17860.
- Background: PubMed 15273990Ame JC, Spenlehauer C, de Murcia G. The PARP superfamily. Bioessays. 2004 Aug;26(8):882-93. doi: 10.1002/bies.20085.
- Background: PubMed 659624Berger NA, Adams JW, Sikorski GW, Petzold SJ, Shearer WT. Synthesis of DNA and poly(adenosine diphosphate ribose) in normal and chronic lymphocytic leukemia lymphocytes. J Clin Invest. 1978 Jul;62(1):111-8. doi: 10.1172/JCI109094.
- Derived from this study: PubMed 21795476Kummar S, Chen A, Ji J, Zhang Y, Reid JM, Ames M, Jia L, Weil M, Speranza G, Murgo AJ, Kinders R, Wang L, Parchment RE, Carter J, Stotler H, Rubinstein L, Hollingshead M, Melillo G, Pommier Y, Bonner W, Tomaszewski JE, Doroshow JH. Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. Cancer Res. 2011 Sep 1;71(17):5626-34. doi: 10.1158/0008-5472.CAN-11-1227. Epub 2011 Jul 27.
Related trials for Solid Tumors
RecruitingPhase 1/2
Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)
Solid Tumor, Non-Small Cell Lung Cancer
Active, not recruitingPhase 1
A Study to Assess Safety, Tolerability, and Pharmacokinetics of ABSK043 in Patients With Advanced Solid Tumor
Neoplasms
Active, not recruitingPhase 3
A Safety and Efficacy Extension Study of Pertuzumab in Patients With Solid Tumors Previously Enrolled in a Hoffmann-La Roche-Sponsored Pertuzumab Clinical Trial
Solid Tumors
RecruitingPhase 1
IL-12 Genetically Engineered Myeloid Cells in Participants With Relapsed, Refractory Solid Tumors
Relapsed Solid Tumor Malignancies, Refractory Solid Tumor Malignancies
RecruitingObservational study
Immune Checkpoint Inhibitor Toxicity Risk Prediction in Solid Tumors
Malignant Solid Neoplasm
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.
The record lists no contact. Use the official record to reach the sponsor.
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 ABT-888 and Topotecan in people with Solid Tumors and Lymphomas, run by National Cancer Institute (NCI) 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 0 inclusion and 5 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 2 Jul 2017. 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?
Safety and tolerability of the combination of ABT-888 with topotecan hydrochloride in patients with refractory solid tumors and lymphomas; Establish the maximum tolerated dose of ABT-888 with topotecan hydrochloride.. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00553189, which also lists 4 linked publications.
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 2 Jul 2017.