Anaplastic AstrocytomasPhase 2NCT01663012
Phase II NKTR-102 In Bevacizumab-Resistant High Grade Glioma
A Phase 2 study testing Etirinotecan pegol in people with Anaplastic Astrocytomas and Anaplastic Oligodendrogliomas, run by Lawrence Recht at 1 site in United States.
Trial summary
High Grade Gliomas, including anaplastic astrocytomas, anaplastic oligodendrogliomas and glioblastomas (GBM), are the most common and most aggressive primary brain tumors. Prognosis for patients with high-grade gliomas remains poor. The estimated median survival for patients with GBM is between 12 to 18 months. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Anaplastic Astrocytomas, Anaplastic Oligodendrogliomas, Glioblastomas (GBM)
- What is being tested?
- Etirinotecan pegol
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2012to Feb 2015
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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
- Pathologically proven high-grade glioma (WHO III or IV) with astrocytic component and must be in recurrence after treatment with bevacizumab
- Patients must have received conventional radiation therapy of total radiation dosage (ranging from 5400 to 6000 cGy administered in daily fractions of 150 to 200 cGy over 6 weeks) with concurrent temozolomide.
- Patients must have received bevacizumab and be in recurrence after bevacizumab treatment.
- Patients must be at least 28 days from last administration of cytotoxic chemotherapy and at least 14 days from the last administration of bevacizumab.
- Patients must be >18 years of age.
- Patients must have a life expectancy > 6 weeks
Show all 18Show fewer
- Patients must have a Karnofsky Performance Score (KPS) >=50
- If female, patients of childbearing potential must have a negative serum beta-hCG pregnancy test and must agree to use hormonal or barrier birth control with spermicidal gel to avoid pregnancy during the study
- Adequate organ function (obtained within 14 days prior to randomization and analyzed by the central laboratory) as evidenced by:
- Absolute neutrophil count (ANC) >=1.5 X 10^9/L without myeloid growth factor support for 7 days preceding the lab assessment;
- Hemoglobin (Hgb) >= 9 g/dL (90 g/L); < 9 g/dL (< 90 g/L) is acceptable if hemoglobin is corrected to >= 9 g/dL (90 g/L) as by growth factor or transfusion prior to randomization;
- Platelet count >=100 X 10^9/L without blood transfusions for 7 days preceding the lab assessment;
- Bilirubin <= 1.5 X upper limit of normal (ULN), except for patients with documented history of Gilbert's disease;
- Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <= 2.5 X ULN
- Alkaline phosphatase (AP) <= 3 X ULN
- Serum creatinine <= 1.5 mg/dL (133 µmol/L) or calculated creatinine clearance >= 50 mL/min (using Cockcroft-Gault formula);
- Women of childbearing potential (WCBP): negative serum pregnancy test (this test is required of all women unless post-menopausal, defined as 12 consecutive months since last regular menses, or surgically sterile).
- Patients must be willing and able to comply with the protocol and provide written informed consent prior to study-specific screening procedures.
Who cannot join
- Patients who meet any of the following criteria must not be permitted entry to the study.
- Patients who have had chemotherapy within 28 days, radiotherapy within 28 days, biological therapy within 14 days, and investigational therapy within 21 days prior to first dose of experimental drug.
- Patients who have received prior treatment for cancer with a camptothecin derivative (eg, irinotecan, topotecan, and investigational agents including but not limited to exatecan, rubitecan, gimatecan, karenitecan, SN38 investigational agents, EZN-2208, SN-2310, and AR-67).
- Patients with the following co-morbid disease or incurrent illness:
- Patients with chronic or acute GI disorders resulting in diarrhea of any severity grade; patients who are using chronic anti-diarrheal supportive care (more than 3 days/week) to control diarrhea in the 28 days prior to first dose of investigational drug.
- Patients with known cirrhosis diagnosed with Child-Pugh Class A or higher liver disease.
Show all 20Show fewer
- Prior malignancy except for non-melanoma skin cancer and carcinoma in situ (of the cervix or bladder), unless diagnosed and definitively treated more than 3 years prior to first dose of investigational drug.
- Severe/uncontrolled inter-current illness within the previous 28 days prior to first dose of investigational drug.
- Significant known cardiovascular impairment (NYHA CHF > grade 2, unstable angina, myocardial infarction within the previous 6 months prior to first dose of investigational drug, or existing serious cardiac arrhythmia).
- Patients who require daily use of oxygen supplementation in the 28 days prior to first dose of investigational drug.
- Any other significant co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation.
- Patients with a known allergy or hypersensitivity to any of the components of the investigational therapy, including PEG or topoisomerase inhibitors.
- Patients receiving the following medications at the time of first dose of investigational drug:
- Pharmacotherapy for hepatitis B or C, tuberculosis, or HIV.
- enzyme inducing anti-epileptic medications (EIAEDs)
- other chemotherapy, other investigational agents , or biologic agents for
- the treatment of cancer including antibodies(eg, bevacizumab,
- trastuzumab, or pertuzumab) or any investigational agent(s).
- Pregnant or nursing patients will be excluded from the study.
- Patients receiving active treatment for HIV will be excluded from this study because non-nucleoside reverse transcriptase inhibitors, protease inhibitors and maraviroc (a CCR5-antagonist) are extensively metabolized by the cytochrome P450 system. Interactions with these drugs may induce or inhibit irinotecan or SN38 metabolism, leading to over or under-dosing.
Trial locations and contacts
1 site in 1 country.
United States1 site
Stanford University School of Medicine
Palo Alto, California, 94305
About this study
Official title: A Phase II, Single Arm, Open Label Study Of NKTR-102 In Bevacizumab-Resistant High Grade Glioma
High Grade Gliomas, including anaplastic astrocytomas, anaplastic oligodendrogliomas and glioblastomas (GBM), are the most common and most aggressive primary brain tumors. Prognosis for patients with high-grade gliomas remains poor. The estimated median survival for patients with GBM is between 12 to 18 months. Recurrence after initial therapy with temozolomide and radiation is nearly universal. Since May 2009, the majority of patients in the US with an initial recurrence of high-grade glioma receive bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), which is thought to prevent angiogenesis in these highly vascular tumors. BEV has response rates from 32-62% and has improved overall median survival in patients with recurrent high-grade gliomas1. However, the response is short lived, and nearly 100% of patients eventually progress despite bevacizumab. No chemotherapeutic agent administered following progression through bevacizumab has made a significant impact on survival. Patients progress to death within 1-5 months after resistance develops. Therefore, patients with high-grade gliomas who have progressed through bevacizumab represent a population in dire need of a feasible and tolerable treatment.
NKTR-102 is a topoisomerase I inhibitor polymer conjugate that was engineered by attaching irinotecan molecules to a polyethylene glycol (PEG) polymer using a biodegradable linker. Irinotecan released from NKTR-102 following administration is further metabolized to the active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN38), that causes DNA damage through inhibition of topoisomerase. The goal in designing NKTR-102 was to attenuate or eliminate some of the limiting side effects of irinotecan while improving efficacy by modifying the distribution of the agent within the body. The size and structure of NKTR-102 results in marked alteration in pharmacokinetic (PK) profile for the SN38 derived from NKTR-102 compared to that following irinotecan: the maximal plasma concentration (Cmax) is reduced 5- to 10-fold and the half-life (t1/2 ) of SN38 is increased from 2 days to approximately 50 days. This altered profile leads to constant exposure of the tumor to the active drug. In addition, the large NKTR-102 molecule does not freely pass out of intact vasculature, which may account for relatively higher concentrations of the compound and the active metabolites in tumor tissues in in vivo models, where the local vasculature may be relatively more permeable. A 145 mg/m2 dose of NKTR-102, the dose intended for use in this phase II clinical trial (and being used in the phase III clinical program), results in approximately the same plasma exposure to SN38 as a 350 mg/m2 dose of irinotecan, but exposure is protracted, resulting in continuous exposure between dosing cycles and lower Cmax. NKTR-102 was therefore developed as a new chemotherapeutic agent that may improve the clinical outcomes of patients.
- Being tested
- Etirinotecan pegol
- Medical subject headings
- Astrocytoma, Oligodendroglioma, Glioblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Etirinotecan pegolDrug
Also called NKTR-102
| Study group | Role | What they receive |
|---|---|---|
| Drug: Etirinotecan pegol | Experimental | 145 mg/m2 dose Receives: Drug: Etirinotecan pegol |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression Free Survival, Assessed by Revised Assessment in Neuro-oncology (RANO) Criteria
Will be described using Kaplan-Meier estimates. The PFS probability at 6 weeks (PFS-6week) will be estimated with an 80% power and 95% confidence intervals (80% in accord with the planned alpha level, 95% for comparability with other studies, confidence intervals based on the Greenwood formula for the variance of a survival probability).
Measured: 6 weeks from first administration of NKTR-102
Secondary outcomes (2)
Survival From the Time of First NKTR-102 Dose for Patients With BEV-resistant Glioma Receiving NKTR-102 to Date of Death
Will be described using Kaplan-Meier estimates.
Measured: From date of first dose of NKTR-102 to date of death, assessed up to 2 years
Overall Survival From Time of Diagnosis
Will be described using Kaplan-Meier estimates.
Measured: From date of pathologic diagnosis/confirmation of high grade glioma to date of death, assessed up to 2 years.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Aug 2012 (estimated)
- Study startJul 2012
- Primary completionFeb 2015
- Study completionFeb 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Anaplastic AstrocytomasStudies 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Lawrence Recht
- Sponsor type
- University, hospital or other
- Collaborators
- Nektar Therapeutics
- Responsible party
- Sponsor-investigator, Lawrence Recht, Stanford University
- Investigators
- Lawrence Recht, MD, Principal investigator, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01663012
- Sponsor's protocol ID
- IRB-24833
- Other IDs
- SU-06212012-10228, NCI-2012-01288, BRN0021
- Status last verified
- Jan 2016
- First submitted
- 2 Aug 2012
- Last updated
- 24 Feb 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 24 Feb 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II, Single Arm, Open Label Study Of NKTR-102 In Bevacizumab-Resistant High Grade Glioma
- ClinicalTrials.gov ID
- NCT01663012
- Acronym / sponsor ID
- IRB-24833
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Lawrence RechtUniversity, hospital or other
- Collaborators
- Nektar Therapeutics
- Study start
- Jul 2012
- Primary completion
- Feb 2015 (actual)
- Study completion
- Feb 2015 (actual)
- First posted
- 13 Aug 2012 (estimated)
- Results
- Posted 11 Jun 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
High Grade Gliomas, including anaplastic astrocytomas, anaplastic oligodendrogliomas and glioblastomas (GBM), are the most common and most aggressive primary brain tumors. Prognosis for patients with high-grade gliomas remains poor. The estimated median survival for patients with GBM is between 12 to 18 months. Recurrence after initial therapy with temozolomide and radiation is nearly universal. Since May 2009, the majority of patients in the US with an initial recurrence of high-grade glioma receive bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), which is thought to prevent angiogenesis in these highly vascular tumors. BEV has response rates from 32-62% and has improved overall median survival in patients with recurrent high-grade gliomas1. However, the response is short lived, and nearly 100% of patients eventually progress despite bevacizumab. No chemotherapeutic agent administered following progression through bevacizumab has made a significant impact on survival. Patients progress to death within 1-5 months after resistance develops. Therefore, patients with high-grade gliomas who have progressed through bevacizumab represent a population in dire need of a feasible and tolerable treatment.
NKTR-102 is a topoisomerase I inhibitor polymer conjugate that was engineered by attaching irinotecan molecules to a polyethylene glycol (PEG) polymer using a biodegradable linker. Irinotecan released from NKTR-102 following administration is further metabolized to the active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN38), that causes DNA damage through inhibition of topoisomerase. The goal in designing NKTR-102 was to attenuate or eliminate some of the limiting side effects of irinotecan while improving efficacy by modifying the distribution of the agent within the body. The size and structure of NKTR-102 results in marked alteration in pharmacokinetic (PK) profile for the SN38 derived from NKTR-102 compared to that following irinotecan: the maximal plasma concentration (Cmax) is reduced 5- to 10-fold and the half-life (t1/2 ) of SN38 is increased from 2 days to approximately 50 days. This altered profile leads to constant exposure of the tumor to the active drug. In addition, the large NKTR-102 molecule does not freely pass out of intact vasculature, which may account for relatively higher concentrations of the compound and the active metabolites in tumor tissues in in vivo models, where the local vasculature may be relatively more permeable. A 145 mg/m2 dose of NKTR-102, the dose intended for use in this phase II clinical trial (and being used in the phase III clinical program), results in approximately the same plasma exposure to SN38 as a 350 mg/m2 dose of irinotecan, but exposure is protracted, resulting in continuous exposure between dosing cycles and lower Cmax. NKTR-102 was therefore developed as a new chemotherapeutic agent that may improve the clinical outcomes of patients.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Drug: Etirinotecan pegol | Experimental | Drug: Etirinotecan pegol145 mg/m2 dose |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- Pathologically proven high-grade glioma (WHO III or IV) with astrocytic component and must be in recurrence after treatment with bevacizumab
- Patients must have received conventional radiation therapy of total radiation dosage (ranging from 5400 to 6000 cGy administered in daily fractions of 150 to 200 cGy over 6 weeks) with concurrent temozolomide.
- Patients must have received bevacizumab and be in recurrence after bevacizumab treatment.
- Patients must be at least 28 days from last administration of cytotoxic chemotherapy and at least 14 days from the last administration of bevacizumab.
Key exclusion criteria (20 listed)
- Patients who meet any of the following criteria must not be permitted entry to the study.
- Patients who have had chemotherapy within 28 days, radiotherapy within 28 days, biological therapy within 14 days, and investigational therapy within 21 days prior to first dose of experimental drug.
- Patients who have received prior treatment for cancer with a camptothecin derivative (eg, irinotecan, topotecan, and investigational agents including but not limited to exatecan, rubitecan, gimatecan, karenitecan, SN38 investigational agents, EZN-2208, SN-2310, and AR-67).
- Patients with the following co-morbid disease or incurrent illness:
- Patients with a known allergy or hypersensitivity to any of the components of the investigational therapy, including PEG or topoisomerase inhibitors.
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 |
|---|---|---|
| Etirinotecan pegolAlso: NKTR-102 | Drug | Drug: Etirinotecan pegol |
Primary outcome
Progression Free Survival, Assessed by Revised Assessment in Neuro-oncology (RANO) Criteria
Time frame: 6 weeks from first administration of NKTR-102
Will be described using Kaplan-Meier estimates. The PFS probability at 6 weeks (PFS-6week) will be estimated with an 80% power and 95% confidence intervals (80% in accord with the planned alpha level, 95% for comparability with other studies, confidence intervals based on the Greenwood formula for the variance of a survival probability).
2 secondary outcomes
Survival From the Time of First NKTR-102 Dose for Patients With BEV-resistant Glioma Receiving NKTR-102 to Date of Death
Time frame: From date of first dose of NKTR-102 to date of death, assessed up to 2 years
Overall Survival From Time of Diagnosis
Time frame: From date of pathologic diagnosis/confirmation of high grade glioma to date of death, assessed up to 2 years.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Feb 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Related trials for Anaplastic Astrocytomas
Active, not recruitingPhase 2
Dabrafenib Combined With Trametinib After Radiation Therapy in Treating Patients With Newly-Diagnosed High-Grade Glioma
Anaplastic Astrocytoma, Anaplastic Astrocytoma, Not Otherwise Specified
RecruitingPhase 1/2
A Study of Zedoresertib (Debio 0123) in Combination With Temozolomide in Adult Participants With Recurrent or Progressive Glioblastoma and of Zedoresertib (Debio 0123) in Combination With Temozolomide and Radiotherapy in Adult Participants With Newly Diagnosed Glioblastoma
Glioblastoma IDH (Isocitrate Dehydrogenase) Wildtype, Astrocytoma, Grade III
RecruitingPhase 1
Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms
Central Nervous System Neoplasms, Glioblastoma
RecruitingEarly Phase 1
Implantable Microdevice In Primary Brain Tumors
Grade II Glioma, Grade III Glioma
Recruiting
Local, Targeted Therapy With Alpha Emitter [225Ac]Ac-DOTA-SP (TAT) in Glioma (WHO G3-G4) Progression
Glioblastoma, High-Grade Gliomas
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.
Lawrence Recht, MD principal investigator
Stanford University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Etirinotecan pegol in people with Anaplastic Astrocytomas and Anaplastic Oligodendrogliomas, run by Lawrence Recht 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 18 inclusion and 20 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 24 Feb 2016. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Jun 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Progression Free Survival, Assessed by Revised Assessment in Neuro-oncology (RANO) Criteria (time frame: 6 weeks from first administration of NKTR-102). 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 24 Feb 2016.