Advanced GlioblastomaPhase 1/2NCT02038699
A First-in-man Phase I/II Study of Oral ONC201 in Patients With Advanced Cancer
A Phase 1/2 study testing ONC201 in people with Advanced Glioblastoma and Advanced Colorectal Cancer, run by Jazz Pharmaceuticals at 1 site in United States.
Trial summary
ONC201 is a new potential drug that kills cancer cells but not normal cells in laboratory studies. This clinical trial will be the first evaluation of ONC201 in humans and will enroll patients with advanced cancer. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Glioblastoma, Advanced Colorectal Cancer, Advanced Triple-negative Breast Cancer
- What is being tested?
- ONC201
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2014to Dec 2016
- Phase
- Phase 1/2
- 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
- Patients must have histologically confirmed glioblastoma multiforme, triple-negative breast cancer, colorectal cancer, or non-small cell lung cancer patients with advanced disease and limited therapeutic options.
- Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. For lymph nodes to be considered measurable, the short axis must be ≥15 mm when assessed by CT scan. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered non-measurable. See Section 11 for the evaluation of measurable disease.
- Patients are eligible for enrollment if they have not had prior chemotherapy, radiotherapy, anticancer therapy, or investigational agent within 28 days prior to the first dose (Week 1, Day 1); 42 days weeks in the case of alkylating agents. Patients are eligible for enrollment if they have had no surgery within 6 weeks prior to the first dose. Any number of prior therapies is allowable.
- All adverse events Grade > 1 related to prior therapies (chemotherapy, radiotherapy, and/or surgery) must be resolved, except for alopecia.
- Age ≥18 years.
- ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix A).
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- Life expectancy of greater than 10 weeks.
- Patients must have normal organ and marrow function as defined below:
- leukocytes ≥ 3,000/mcL
- absolute neutrophil count ≥ 1,500/mcL
- platelets ≥ 100,000/mcL
- hemoglobin > 8.0 mg/dL
- total bilirubin < 2.0 x upper limit of normal
- AST (SGOT)/ALT (SGPT) ≤2.5 × upper limit of normal creatinine OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above normal.
- The effects of ONC201 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
- Tumor specimen (paraffin-embedded block or frozen tissue) from prior resection or biopsy available that is sufficient to perform pharmacodynamic assays (>3 slides for IHC)
- Ability to understand and the willingness to sign a written informed consent document.
Who cannot join
- Patients who have received bevacizumab therapy.
- Patients with known brain metastases will be excluded from the phase I portion of the study. In the phase II portion, patients with known CNS metastases will be limited to 20% of the patient population to accrue proportionately. Patients with CNS metastases must be stable after therapy for CNS metastases (such as surgery, radiotherapy or stereotactic radiosurgery) for > 3 month and must be off steroid treatment prior to study enrollment and must have a life expectancy of 3 months or greater to be eligible.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC201 or its excipients.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant women are excluded from this study because ONC201 is novel agent with unknown potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ONC201, breastfeeding should be discontinued if the mother is treated with ONC201.
- Patients with a known HIV-positive test on combination antiretroviral therapy are ineligible for the initial first-in-man trial because of the potential for pharmacokinetic interactions with ONC201. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
- Patients with known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias or bradycardia will be excluded. Patients receiving therapeutic agents known to prolong QT interval will be excluded. Patients with history of CHF, or MI or stroke in the last 3 months will be excluded. Patients with a history of seizures will be excluded form the initial trial because ONC201 crosses the blood-brain barrier and this may affect their anti-seizure therapy.
- Active drug use or alcoholism.
Trial locations and contacts
1 site in 1 country.
United States1 site
Massachusetts General Hospital
Boston, Massachusetts, 02114
About this study
Official title: A First-in-man Phase I/II Single-agent Open-label Dose-escalation Study of Every Three-week Dosing of Oral ONC201 in Patients With Advanced Cancer and Limited Treatment Options
ONC201 is a new potential drug that kills cancer cells but not normal cells in laboratory studies. This clinical trial will be the first evaluation of ONC201 in humans and will enroll patients with advanced cancer. This trial includes a phase I portion that will evaluate the safety of ONC201 and the recommended dose for the phase II portion. The phase II portion will evaluate the initial efficacy profile of ONC201 in select types of cancer.
Read the detailed description
ONC201 (TIC10) is a first-in-class small molecule that inactivates the Ras effector target kinases, Akt and ERK, selectively in tumor, but not normal, cells to safely trigger cancer cell death. The dual inactivation of Akt and ERK by ONC201 results in broad-spectrum cytotoxic activity that includes activation of TRAIL-mediated apoptotic and other downstream antitumor effects to produce a potent antitumor response. The safety margin (ratio of therapeutic dose to lowest dose with a mild adverse event) of ONC201 is at least 10-fold in rats and dogs in GLP toxicology. The efficacy of ONC201 has been consistently demonstrated in multiple in vitro, ex vivo, and in vivo preclinical cancer models. Favorable attributes of ONC201 observed in preclinical models include antitumor efficacy with infrequent administration, broad-spectrum activity independent of mutations or tumor type, orally active, high safety margins, synergistic activity with many approved therapies, highly stable, highly water soluble, and ability to penetrate the blood-brain barrier. In the phase I portion of the trial, the hypothesis is that ONC201 will exhibit an acceptable safety profile in patients with advanced cancer. In the phase II portion of the trial, the hypothesis is that ONC201 will show preliminary signs of efficacy in patients with advanced cancer as defined by endpoints that include progression-free survival, response rate, biomarkers, and overall survival.
- Conditions
- Advanced Glioblastoma, Advanced Colorectal Cancer, Advanced Triple-negative Breast Cancer, Advanced Non-small Cell Lung Cancer
- Being tested
- ONC201
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ONC201Drug
Also called TIC10
ONC201 capsules will be administered orally once every three weeks with flat dosing. Dosage will be given according to a modified Fibonacci sequence with the anticipated starting dose being 125 mg.
| Study group | Role | What they receive |
|---|---|---|
| ONC201 | Experimental | Oral ONC201 will be administered once every three weeks at various doses. Receives: Drug: ONC201 |
What is being measured
The primary outcome is the main question the study is designed to answer.
In Phase I, to determine the recommended phase II doses of ONC201.
Measured: Participants will be followed for the duration of the study, an expected average of 6 months.
In phase II, Progression-free survival of patients treated with ONC201.
Measured: from enrollment until first documented progression or date of death from any cause, whichever came first, assessed up to 100 months.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jan 2014 (estimated)
- Study startJan 2014 (estimated)
- Primary completionDec 2015 (estimated)
- Study completionDec 2016 (estimated)
Why it stopped: Protocol not activated.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Advanced GlioblastomaStudies of the same condition, open and under way.
- More trials run by Jazz PharmaceuticalsThe 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 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jazz Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Jason Faris, MD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02038699
- Sponsor's protocol ID
- 00001
- Status last verified
- Oct 2014
- First submitted
- 14 Jan 2014
- Last updated
- 30 Apr 2021
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 30 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A First-in-man Phase I/II Single-agent Open-label Dose-escalation Study of Every Three-week Dosing of Oral ONC201 in Patients With Advanced Cancer and Limited Treatment Options
- ClinicalTrials.gov ID
- NCT02038699
- Acronym / sponsor ID
- 00001
- Conditions
- Advanced Glioblastoma, Advanced Colorectal Cancer, Advanced Triple-negative Breast Cancer, Advanced Non-small Cell Lung Cancer
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Protocol not activated.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Jazz PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- Jan 2014 (estimated)
- Primary completion
- Dec 2015 (estimated)
- Study completion
- Dec 2016 (estimated)
- First posted
- 16 Jan 2014 (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.
ONC201 is a new potential drug that kills cancer cells but not normal cells in laboratory studies. This clinical trial will be the first evaluation of ONC201 in humans and will enroll patients with advanced cancer. This trial includes a phase I portion that will evaluate the safety of ONC201 and the recommended dose for the phase II portion. The phase II portion will evaluate the initial efficacy profile of ONC201 in select types of cancer.
Detailed description
ONC201 (TIC10) is a first-in-class small molecule that inactivates the Ras effector target kinases, Akt and ERK, selectively in tumor, but not normal, cells to safely trigger cancer cell death. The dual inactivation of Akt and ERK by ONC201 results in broad-spectrum cytotoxic activity that includes activation of TRAIL-mediated apoptotic and other downstream antitumor effects to produce a potent antitumor response. The safety margin (ratio of therapeutic dose to lowest dose with a mild adverse event) of ONC201 is at least 10-fold in rats and dogs in GLP toxicology. The efficacy of ONC201 has been consistently demonstrated in multiple in vitro, ex vivo, and in vivo preclinical cancer models. Favorable attributes of ONC201 observed in preclinical models include antitumor efficacy with infrequent administration, broad-spectrum activity independent of mutations or tumor type, orally active, high safety margins, synergistic activity with many approved therapies, highly stable, highly water soluble, and ability to penetrate the blood-brain barrier. In the phase I portion of the trial, the hypothesis is that ONC201 will exhibit an acceptable safety profile in patients with advanced cancer. In the phase II portion of the trial, the hypothesis is that ONC201 will show preliminary signs of efficacy in patients with advanced cancer as defined by endpoints that include progression-free survival, response rate, biomarkers, and overall survival.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| ONC201 | Experimental | Drug: ONC201Oral ONC201 will be administered once every three weeks at various doses. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- Patients must have histologically confirmed glioblastoma multiforme, triple-negative breast cancer, colorectal cancer, or non-small cell lung cancer patients with advanced disease and limited therapeutic options.
- Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. For lymph nodes to be considered measurable, the short axis must be ≥15 mm when assessed by CT scan. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered non-measurable. See Section 11 for the evaluation of measurable disease.
- Patients are eligible for enrollment if they have not had prior chemotherapy, radiotherapy, anticancer therapy, or investigational agent within 28 days prior to the first dose (Week 1, Day 1); 42 days weeks in the case of alkylating agents. Patients are eligible for enrollment if they have had no surgery within 6 weeks prior to the first dose. Any number of prior therapies is allowable.
- All adverse events Grade > 1 related to prior therapies (chemotherapy, radiotherapy, and/or surgery) must be resolved, except for alopecia.
- Age ≥18 years.
Key exclusion criteria (8 listed)
- Patients who have received bevacizumab therapy.
- Patients with known brain metastases will be excluded from the phase I portion of the study. In the phase II portion, patients with known CNS metastases will be limited to 20% of the patient population to accrue proportionately. Patients with CNS metastases must be stable after therapy for CNS metastases (such as surgery, radiotherapy or stereotactic radiosurgery) for > 3 month and must be off steroid treatment prior to study enrollment and must have a life expectancy of 3 months or greater to be eligible.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC201 or its excipients.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant women are excluded from this study because ONC201 is novel agent with unknown potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ONC201, breastfeeding should be discontinued if the mother is treated with ONC201.
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 |
|---|---|---|
| ONC201Also: TIC10ONC201 capsules will be administered orally once every three weeks with flat dosing. Dosage will be given according to a modified Fibonacci sequence with the anticipated starting dose being 125 mg. | Drug | ONC201 |
Primary outcome
In Phase I, to determine the recommended phase II doses of ONC201.
Time frame: Participants will be followed for the duration of the study, an expected average of 6 months.
In phase II, Progression-free survival of patients treated with ONC201.
Time frame: from enrollment until first documented progression or date of death from any cause, whichever came first, assessed up to 100 months.
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Apr 2021.
- Sponsor website.Link provided by the sponsor.
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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.
Jason Faris, MD principal investigator
Massachusetts General Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing ONC201 in people with Advanced Glioblastoma and Advanced Colorectal Cancer, run by Jazz Pharmaceuticals 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 17 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: withdrawn, as of the sponsor's last update on 30 Apr 2021. 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 combined 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.
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?
The study was withdrawn before enrolling participants, so there are no results.
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?
In Phase I, to determine the recommended phase II doses of ONC201. (time frame: Participants will be followed for the duration of the study, an expected average of 6 months.). 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 30 Apr 2021.