NeoplasmsPhase 1NCT01445522
ABT-888 Plus Metronomic Cyclophosphamide to Treat Cancer
A Phase 1 study testing ABT-888 and Cyclophosphamide in people with Neoplasms and Lymphoma, run by National Cancer Institute (NCI) at 2 sites in United States.
Trial summary
Background: Cyclophosphamide (CP) is a drug approved by the Food and Drug Administration for the treatment of certain cancers. It works by causing DNA damage, resulting in cell death, including cancer cells. ABT-888 is an experimental drug that has been given to a small number of patients. Read more about this study
- Who is it for?
- Ages 18 to 110 years
- What is being tested?
- ABT-888 and Cyclophosphamide
- How many people
- 35 participants
- Where
- 2 sitesUnited States
- Study dates
- 3 Dec 2008to 3 Jul 2012
- 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 to 110 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with histologically documented solid tumors or lymphoid malignancies (lymphoma and CLL) refractory to standard therapy or who have no acceptable standard treatment options. Patients with lymphoid malignancies will be eligible if their disease has progressed following standard therapy and if stem cell transplantation is not indicated or has been refused.
- Any prior therapy must have been completed greater than or equal to 4 weeks (greater than 6 weeks for nitrosoureas or mitomycin C) prior to enrollment on protocol, and the participant must have recovered to eligibility levels (CTCAE Grade less than or equal to 1) from prior toxicity. Prior radiation should have been completed greater than or equal to 4 weeks prior to study enrollment, and all associated toxicities should have resolved to eligibility levels. 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.
- Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of ABT-888 in patients less than 18 years of age, children are excluded from this study, but may be eligible for future pediatric Phase I combination trials.
- Karnofsky performance status greater than or equal to 60%, see Appendix A.
- Life expectancy of greater than 3 months.
- Patients must have normal organ and marrow function as defined below:
Show all 15Show fewer
- absolute neutrophil count greater than or equal to 1,500/microL (mcL)
- platelets greater than or equal to 100,000/microL (mcL)
- total bilirubin less than 1.5 times the institutional upper limit of normal
- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times the institutional upper limit of normal
- creatinine less than 1.5 times the institutional upper limit of normal
- OR
- creatinine clearance greater than or equal to 60 mL/min for patients with creatinine levels 1.5 times the institutional upper limit of normal.
- The effects of ABT-888 on the developing human fetus are unknown. For this reason and because cyclophosphamide hydrochloride used in this trial is known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (abstinence; female use of hormonal methods, or barrier methods of birth control; male use of a condom) prior to study entry, for the duration of study participation, and for 3 months after completion of study. Because there is a risk for adverse events in nursing infants secondary to treatment of the mother with cyclophosphamide, breastfeeding should be discontinued while the patient is on this trial and for 30 days after completion of treatment on this trial. 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 the willingness to sign a written informed consent document.
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 cyclophosphamide should not be excluded solely because of receiving prior cyclophosphamide.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- Patients with gliomas, symptomatic CNS metastases or carcinomatous meningitis are excluded from this clinical trial. Patients with history of CNS metastases who have received treatment and whose CNS metastatic disease status has remained stable for greater than or equal to 3 months without steroids or anti-seizure medications may be eligible. These patients may be enrolled at the discretion of the principal investigator.
- Patients with a history of seizures.
- Patients with HIV who are taking protease inhibitors.
- Patients with gastrointestinal conditions that might predispose for drug intolerability or poor drug absorption (e.g., inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, malabsorption syndrome, active peptic ulcer disease) are excluded. Subjects with ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel obstruction are also excluded.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
City of Hope National Medical Center
Duarte, California, 91010
About this study
Official title: A Phase I Study of ABT-888 in Combination With Metronomic Cyclophosphamide in Adults With Refractory Solid Tumors and Lymphomas
Background:
- Cyclophosphamide (CP) is a drug approved by the Food and Drug Administration for the treatment of certain cancers. It works by causing DNA damage, resulting in cell death, including cancer cells.
- ABT-888 is an experimental drug that has been given to a small number of patients. It works by preventing DNA repair in tumor cells.
Read more
Objectives:
- To test the safety of the combination of ABT-888 and CP, and to determine the dose of each drug that can be given together to patients with cancer.
- To see how the body handles ABT-888 when given together with CP
- To evaluate the anti-tumor response of the drug combination.
Eligibility:
- Adults with solid tumors or lymphoid cancers (lymphoma and chronic lymphocytic leukemia) whose disease does not respond to standard treatments.
Design:
- Patients take ABT-888 by mouth once a day for 7, 14 or 21 days, depending on the dose level assigned to the individual patient.
- Patients take CP by mouth once a day every day in 21-day cycles. (Some patients take CP for 14 days only.)
- Patients undergo tests and procedures periodically during the study, including:
- Clinic visit and physical examination at the beginning of each cycle
- Blood and urine tests, electrocardiogram, measurement of vital signs
- CT scans, MRI scans or ultrasound tests to check the response of the tumor to treatment
- Tumor biopsies (optional)
- Bone marrow aspiration and biopsy
Read the detailed description
Background:
- The poly (ADP-ribose) polymerase (PARP) family of enzymes is characterized by the ability to poly-ADP-ribosylate 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.
- PARP activity has been shown to be important in base excision repair pathways. The inhibition of PARP could inhibit the repair of the DNA damage caused by alkylating agents such as cyclophosphamide. ABT-888 has been shown to potentiate the action of cyclophosphamide in xenografts models. ABT-888 is an orally delivered PARP inhibitor and cyclophosphamide can be delivered orally as an alkylating agent.
- Metronomic therapy with cyclophosphamide has demonstrated efficacy in multiple tumor types including, but not limited to, ovarian cancer, lymphoma, prostate cancer, and breast cancer. Its activity has been at least partially attributed to mediation of anti-angiogenic effects through induction of apoptosis in endothelial cells.
Objectives:
- Establish the safety and tolerability of the combination of ABT-888 with metronomic cyclophosphamide in patients with refractory solid tumors and lymphomas.
- Establish the maximum tolerated dose (MTD) of the combination of ABT-888 with metronomic cyclophosphamide.
- Evaluate the pharmacokinetics of ABT-888 when administered combination with cyclophosphamide.
- Evaluate for anti-tumor response.
- Determine the effects of the study treatment on the level of PARP inhibition and gamma-H2AX in PBMCs and tumor samples.
Eligibility:
- Patients with histologically documented solid tumors or 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:
- ABT-888 will be administered orally once daily for 7 to 21 days, depending on the dose level (see below). Cyclophosphamide will be administered orally once daily in 50 mg or 100 mg doses continuously from days 1 to 21. Cycle length is 21 days.
- Dose escalation will proceed as outlined below. Once MTD is established, 6 additional patients will be enrolled at the MTD to evaluate that dose further and extend PD studies at that dose level.
- Being tested
- ABT-888, Cyclophosphamide
- Keywords
- PARP Inhibitor, DNA Damage, Chemotherapy, Advanced Cancer, DNA Repair
- Medical subject headings
- Neoplasms, Lymphoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ABT-888Drug
CyclophosphamideDrug
What is being measured
The primary outcome is the main question the study is designed to answer.
Establish the safety and tolerability of the combination of ABT-888 with metronomic cyclophosphamide in patients with refractory solid tumors and lymphomas. Establish the MTD of the combination of ABT-888 with metronomic cyclophosphamide.
Secondary outcomes (1)
Evaluate the pharmacokinetics of ABT-888 when administered combination with cyclophosphamide. Evaluate for anti-tumor response.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Oct 2011 (estimated)
- Study start3 Dec 2008
- Primary completion3 Jul 2012
- Study completion3 Jul 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for NeoplasmsStudies 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
- Single group
- Masking
- None (open label)
- Enrolment
- 35 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Investigators
- Shivaani Kummar, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01445522
- Sponsor's protocol ID
- 090048
- Other IDs
- 09-C-0048
- Status last verified
- 29 Jun 2012
- First submitted
- 30 Sep 2011
- Last updated
- 17 Dec 2019
- Results posted
- No
Publications
Alderson T. New targets for cancer chemotherapy--poly(ADP-ribosylation) processing and polyisoprene metabolism. Biol Rev Camb Philos Soc. 1990 Nov;65(4):623-41. doi: 10.1111/j.1469-185x.1990.tb01240.x. No abstract available.
PubMed 2124932Ame 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 15273990
Study at a glance
From the registry record, last updated by the sponsor on 17 Dec 2019. 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 Metronomic Cyclophosphamide in Adults With Refractory Solid Tumors and Lymphomas
- ClinicalTrials.gov ID
- NCT01445522
- Acronym / sponsor ID
- 090048
- Keywords
- PARP Inhibitor, DNA Damage, Chemotherapy, Advanced Cancer, DNA Repair
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 35 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 3 Dec 2008
- Primary completion
- 3 Jul 2012 (actual)
- Study completion
- 3 Jul 2012 (actual)
- First posted
- 3 Oct 2011 (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:
- Cyclophosphamide (CP) is a drug approved by the Food and Drug Administration for the treatment of certain cancers. It works by causing DNA damage, resulting in cell death, including cancer cells.
- ABT-888 is an experimental drug that has been given to a small number of patients. It works by preventing DNA repair in tumor cells.
Objectives:
- To test the safety of the combination of ABT-888 and CP, and to determine the dose of each drug that can be given together to patients with cancer.
- To see how the body handles ABT-888 when given together with CP
- To evaluate the anti-tumor response of the drug combination.
Eligibility:
- Adults with solid tumors or lymphoid cancers (lymphoma and chronic lymphocytic leukemia) whose disease does not respond to standard treatments.
Design:
- Patients take ABT-888 by mouth once a day for 7, 14 or 21 days, depending on the dose level assigned to the individual patient.
- Patients take CP by mouth once a day every day in 21-day cycles. (Some patients take CP for 14 days only.)
- Patients undergo tests and procedures periodically during the study, including:
- Clinic visit and physical examination at the beginning of each cycle
- Blood and urine tests, electrocardiogram, measurement of vital signs
- CT scans, MRI scans or ultrasound tests to check the response of the tumor to treatment
- Tumor biopsies (optional)
- Bone marrow aspiration and biopsy
Detailed description
Background:
- The poly (ADP-ribose) polymerase (PARP) family of enzymes is characterized by the ability to poly-ADP-ribosylate 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.
- PARP activity has been shown to be important in base excision repair pathways. The inhibition of PARP could inhibit the repair of the DNA damage caused by alkylating agents such as cyclophosphamide. ABT-888 has been shown to potentiate the action of cyclophosphamide in xenografts models. ABT-888 is an orally delivered PARP inhibitor and cyclophosphamide can be delivered orally as an alkylating agent.
- Metronomic therapy with cyclophosphamide has demonstrated efficacy in multiple tumor types including, but not limited to, ovarian cancer, lymphoma, prostate cancer, and breast cancer. Its activity has been at least partially attributed to mediation of anti-angiogenic effects through induction of apoptosis in endothelial cells.
Objectives:
- Establish the safety and tolerability of the combination of ABT-888 with metronomic cyclophosphamide in patients with refractory solid tumors and lymphomas.
- Establish the maximum tolerated dose (MTD) of the combination of ABT-888 with metronomic cyclophosphamide.
- Evaluate the pharmacokinetics of ABT-888 when administered combination with cyclophosphamide.
- Evaluate for anti-tumor response.
- Determine the effects of the study treatment on the level of PARP inhibition and gamma-H2AX in PBMCs and tumor samples.
Eligibility:
- Patients with histologically documented solid tumors or 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:
- ABT-888 will be administered orally once daily for 7 to 21 days, depending on the dose level (see below). Cyclophosphamide will be administered orally once daily in 50 mg or 100 mg doses continuously from days 1 to 21. Cycle length is 21 days.
- Dose escalation will proceed as outlined below. Once MTD is established, 6 additional patients will be enrolled at the MTD to evaluate that dose further and extend PD studies at that dose level.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 18 to 110 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- Patients with histologically documented solid tumors or lymphoid malignancies (lymphoma and CLL) refractory to standard therapy or who have no acceptable standard treatment options. Patients with lymphoid malignancies will be eligible if their disease has progressed following standard therapy and if stem cell transplantation is not indicated or has been refused.
- Any prior therapy must have been completed greater than or equal to 4 weeks (greater than 6 weeks for nitrosoureas or mitomycin C) prior to enrollment on protocol, and the participant must have recovered to eligibility levels (CTCAE Grade less than or equal to 1) from prior toxicity. Prior radiation should have been completed greater than or equal to 4 weeks prior to study enrollment, and all associated toxicities should have resolved to eligibility levels. 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.
- Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of ABT-888 in patients less than 18 years of age, children are excluded from this study, but may be eligible for future pediatric Phase I combination trials.
- Karnofsky performance status greater than or equal to 60%, see Appendix A.
- Life expectancy of greater than 3 months.
Key exclusion criteria (8 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 cyclophosphamide should not be excluded solely because of receiving prior cyclophosphamide.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- Patients with gliomas, symptomatic CNS metastases or carcinomatous meningitis are excluded from this clinical trial. Patients with history of CNS metastases who have received treatment and whose CNS metastatic disease status has remained stable for greater than or equal to 3 months without steroids or anti-seizure medications may be eligible. These patients may be enrolled at the discretion of the principal investigator.
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 | – |
| Cyclophosphamide | Drug | – |
Primary outcome
Establish the safety and tolerability of the combination of ABT-888 with metronomic cyclophosphamide in patients with refractory solid tumors and lymphomas. Establish the MTD of the combination of ABT-888 with metronomic cyclophosphamide.
1 secondary outcome
Evaluate the pharmacokinetics of ABT-888 when administered combination with cyclophosphamide. Evaluate for anti-tumor response.
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 17 Dec 2019.
- Background: PubMed 2124932Alderson T. New targets for cancer chemotherapy--poly(ADP-ribosylation) processing and polyisoprene metabolism. Biol Rev Camb Philos Soc. 1990 Nov;65(4):623-41. doi: 10.1111/j.1469-185x.1990.tb01240.x. No abstract available.
- 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.
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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.
Shivaani Kummar, M.D. principal investigator
National Cancer Institute (NCI)
2 sites 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 Cyclophosphamide in people with Neoplasms and Lymphoma, run by National Cancer Institute (NCI) at 2 sites 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 15 inclusion and 8 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 17 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites 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?
Establish the safety and tolerability of the combination of ABT-888 with metronomic cyclophosphamide in patients with refractory solid tumors and lymphomas. Establish the MTD of the combination of ABT-888 with metronomic cyclophosphamide.. 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 NCT01445522, which also lists 3 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 17 Dec 2019.