Nasopharyngeal Carcinoma, Lymphomas, Any EBV+ Solid TumourPhase 1NCT01341834
Safety and Tolerability Study of RAD001 and LBH589 in All Solid Tumors With Enrichment for EBV Driven Tumors
A Phase 1 study testing LBH589 and RAD001 in people with Nasopharyngeal Carcinoma, Lymphomas, Any EBV+ Solid Tumour, run by National Cancer Centre, Singapore at 1 site in Singapore.
Trial summary
The purpose of this study is: 1. To determine the optimal recommended phase II dose of two investigational study drugs, LBH589 and RAD001, given in combination in all solid tumors (With enrichment for EBV-Driven tumors). 2. To determine the pharmacokinetic profile of RAD001 in combination with two schedules of LBH589. Read more about this study
- Who is it for?
- Ages 21 years and older
- Conditions the study is for
- Nasopharyngeal Carcinoma, Lymphomas, Any EBV+ Solid Tumour
- What is being tested?
- LBH589 and RAD001
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 49 participants
- Where
- 1 siteSingapore
- Study dates
- Mar 2010to Dec 2018
- 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 21 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with histologically or cytologically confirmed solid malignancy or lymphoma that is metastatic or unresectable, and for which standard curative or palliative measures do not exist or are no longer effective.
- For enrichment and dose expansion phase only:
- Only patients with EBV-related tumors, including all nasopharyngeal carcinoma, as well as tumors known to be EBV-related which include (but are not limited to) gastric carcinoma (10-15%), lymphoma. These tumors (NPC excluded) should have:
- i)EBER in situ hybridisation on paraffin samples/ circulating tumor cells; or ii)Elevated pre-treatment serum EBV viral titres
- Patients who have had prior treatment with mTOR inhibitors and HDAC inhibitors will be allowed ONLY in the dose escalation phase
- Age ≥ 21 years old.
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- Performance status of ≤ 2 (ECOG scale).
- Target lesion on spiral CT or MRI scan must have at least one diameter > 1 cm (on conventional CT scan the indicator lesion must have at least one diameter > 2 cm) (for dose expansion).
- Adequate bone marrow reserve: absolute granulocyte count > 1 x 109/L, hemoglobin > 8 g/dL and platelet count >100,000/dL.
- Adequate hepatic function (serum total bilirubin level < 1.5 x ULN; alanine transaminase (ALT) and aspartate transaminase (AST) less than 3 times ULN.
- Adequate renal function (creatinine < 1.5 times ULN).
- Normal ECG at baseline - with no significant conduction abnormalities and a QTc ≤ 450.
- Left Ventricular Ejection Fraction ≥ 50% as assessed by MUGA scan or echocardiography at screening.
- No concurrent use of investigational antineoplastic therapy.
- No medical problems severe enough to prevent compliance with the study requirements
- Negative pregnancy test (urinary β-HCG) at screening (applicable to women of child bearing potential who are sexually active).
- Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
Who cannot join
- Known brain metastases (locally advanced NPC with direct extension to central nervous system is permissible).
- Chemotherapy (in the case of nitrosoureas and mitomycin C within 6 weeks), radiotherapy, immunotherapy within 4 weeks before study drug administration.
- Patients receiving chronic immunosuppressive treatment with high dose corticosteroids (tailing doses or low doses are acceptable) or another immunosuppressive agent;
- Patients with uncontrolled diabetes (fasting glucose > 2x ULN);
- History of uncontrolled heart disease (unstable angina, congestive heart failure, myocardial infarction within preceding 12 months, clinically significant rhythm or conduction abnormality such as second and third degree heart block, congenital long QT syndrome, obligate use of a cardiac pacemaker. Patients with QTc at screening > 450 ms.
- Subjects taking medications known to have a risk of causing causing QTc prolongation and Torsades de Pointes (risk group 1 as indicated on webpage: http://www.torsades.org).
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- Patients who will need valproic acid for any medical condition during the study or within 5 days prior to the first panobinostat treatment.
- Patients with impairment of GI function or GI disease that may significantly alter panobinostat absorption.
- Patients with unresolved diarrhea of grade 2 and above.
- Patients with a known history of Hepatitis B, C and HIV seropositivity.
- Patients with an active bleeding diathesis;
- Subjects with Grade ≥ 2 neuropathy at baseline.
- For patients undergoing magnetic resonance imaging (MRI) studies (including DCE-MRI, BOLD-MRI and DWI-MRI) in the expansion cohort:
- Contraindications to MRI, e.g. contraindicated metal implants
- Patients with poor antecubital fossa venous access.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Safety and Tolerability Study of RAD001 (mTOR Inhibitor) in Combination With Two Dosing Schedules of LBH589B (Histone Deacetylase Inhibitor) in Solid Tumors/ Lymphomas With Enrichment for EBV-Driven Tumors
The purpose of this study is:
- To determine the optimal recommended phase II dose of two investigational study drugs, LBH589 and RAD001, given in combination in all solid tumors (With enrichment for EBV-Driven tumors).
- To determine the pharmacokinetic profile of RAD001 in combination with two schedules of LBH589.
- To assess the preliminary anti-tumor activity of RAD001 and LBH589.
This study will also be exploring the hypothesis that HDACi and mTOR inhibitors abrogate the effects of key viral proteins, and switch the virus from a latent proliferative phase to a lytic phase. Immunologic correlates will also be examined to ascertain T-cell subpopulations and expression of HLA class molecules. DCE-MRI will be subsequently employed in dose expansion to examine antiangiogenic effects.
Read the detailed description
Dose escalation phase 1B of the study will evaluate the safety and tolerability of RAD001 in combination with LBH589 in all solid tumors, lymphomas; and enriched for EBV driven tumors. The phase 2 component will be a single arm, non-randomized study restricted to nasopharyngeal carinoma only (endemic type).
A "3+3" dose escalation design will be adopted. Patients will start taking LBH589 three times a week and will have a run in period of one week, followed by continous administration of RAD001 from week 2. Pharmacokinetic assessments will be done on day 1 of LBH589 administration and day 1 of concurrent administration of LBH589 + RAD001. ON day 31, there will be a one week drug holiday. This is done to explore the eliminaition kinetics from steady state,as well as the durability of target modulation.
AEs of patients will be monitored closely. In the event of grade 3/4 toxicity, the cohort will be expanded to 6. Dose escalation of LBH589/RAD001 may proceed until the maximum tolerated dose (MTD)is reached. Once the MTD is established, an expasion cohort comprising 20 EBV driven tumors will open at two different LBH589 dose schedules.
Treatment will be continued until progression of disease, unacceptable toxcity, or discontinuation criterion is met.
- Being tested
- LBH589 and RAD001
- Keywords
- Nasopharyngeal carcinoma, antiangiogenesis, HDACi, mTOR, Phase Ib
- Medical subject headings
- Nasopharyngeal Carcinoma, Lymphoma, Hereditary Sensory and Autonomic Neuropathies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LBH589 and RAD001Drug
Dose escalation of LBH589 tablets (5 and 10 mg) and RAD001 tablets (2.5, 5 mg and 10mg)
| Study group | Role | What they receive |
|---|---|---|
| LBH589-RAD001 | Experimental | LBH589-RAD001, single arm dose finding study Receives: Drug: LBH589 and RAD001 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety and tolerability
Patients will be followed closely for toxicities in the first cycle where they would have weekly consultations visit. After the first cycle, consultation visits will be once every 2 weeks or once a month depending on how well the patient is tolerating the treatment.
The following safety assesments will be done on every visit; Vital signs and physical examination Haematology and blood chemistry Cardiac monitoring EBV DNA titre (for patients with EBV Driven tumors recording of adverse events and serious adverse events.
Measured: Weekly evaluation for the first 5 weeks (DLT period), and continued follow up until patients come off trial due to toxicity or progressive disease
Secondary outcomes (1)
Tumor response
Tumor response will be evaluated at the end of every 8-weeks of treatment. Treatment will continue until one of the following occur; disease progression, unacceptable toxicity, death, or withdrawal from study. Best response (according to RECIST), as well as progression free survival will be reported.
Measured: Every 2 months until disease progression or withdrawal from study - average of 6 - 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Apr 2011 (estimated)
- Study startMar 2010
- Primary completionJun 2016
- Study completionDec 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Nasopharyngeal Carcinoma, Lymphomas, Any EBV+ Solid TumourStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 49 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Centre, Singapore
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis
- Responsible party
- Sponsor
- Investigators
- Daniel Tan Shao Weng, Principal investigator, National Cancer Center Singapore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01341834
- Sponsor's protocol ID
- 10-01-ST_ECRU
- Status last verified
- Apr 2018
- First submitted
- 21 Apr 2011
- Last updated
- 24 Apr 2018
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 24 Apr 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Safety and Tolerability Study of RAD001 (mTOR Inhibitor) in Combination With Two Dosing Schedules of LBH589B (Histone Deacetylase Inhibitor) in Solid Tumors/ Lymphomas With Enrichment for EBV-Driven Tumors
- ClinicalTrials.gov ID
- NCT01341834
- Acronym / sponsor ID
- 10-01-ST_ECRU
- Keywords
- Nasopharyngeal carcinoma, antiangiogenesis, HDACi, mTOR, Phase Ib
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 49 participants (actual)
- Lead sponsor
- National Cancer Centre, SingaporeUniversity, hospital or other
- Collaborators
- Novartis
- Study start
- Mar 2010 (actual)
- Primary completion
- Jun 2016 (actual)
- Study completion
- Dec 2018 (estimated)
- First posted
- 26 Apr 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.
The purpose of this study is:
- To determine the optimal recommended phase II dose of two investigational study drugs, LBH589 and RAD001, given in combination in all solid tumors (With enrichment for EBV-Driven tumors).
- To determine the pharmacokinetic profile of RAD001 in combination with two schedules of LBH589.
- To assess the preliminary anti-tumor activity of RAD001 and LBH589.
This study will also be exploring the hypothesis that HDACi and mTOR inhibitors abrogate the effects of key viral proteins, and switch the virus from a latent proliferative phase to a lytic phase. Immunologic correlates will also be examined to ascertain T-cell subpopulations and expression of HLA class molecules. DCE-MRI will be subsequently employed in dose expansion to examine antiangiogenic effects.
Detailed description
Dose escalation phase 1B of the study will evaluate the safety and tolerability of RAD001 in combination with LBH589 in all solid tumors, lymphomas; and enriched for EBV driven tumors. The phase 2 component will be a single arm, non-randomized study restricted to nasopharyngeal carinoma only (endemic type).
A "3+3" dose escalation design will be adopted. Patients will start taking LBH589 three times a week and will have a run in period of one week, followed by continous administration of RAD001 from week 2. Pharmacokinetic assessments will be done on day 1 of LBH589 administration and day 1 of concurrent administration of LBH589 + RAD001. ON day 31, there will be a one week drug holiday. This is done to explore the eliminaition kinetics from steady state,as well as the durability of target modulation.
AEs of patients will be monitored closely. In the event of grade 3/4 toxicity, the cohort will be expanded to 6. Dose escalation of LBH589/RAD001 may proceed until the maximum tolerated dose (MTD)is reached. Once the MTD is established, an expasion cohort comprising 20 EBV driven tumors will open at two different LBH589 dose schedules.
Treatment will be continued until progression of disease, unacceptable toxcity, or discontinuation criterion is met.
Study design
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| LBH589-RAD001 | Experimental | Drug: LBH589 and RAD001LBH589-RAD001, single arm dose finding study |
Who may qualify
- Ages
- 21 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- Patients with histologically or cytologically confirmed solid malignancy or lymphoma that is metastatic or unresectable, and for which standard curative or palliative measures do not exist or are no longer effective.
- Only patients with EBV-related tumors, including all nasopharyngeal carcinoma, as well as tumors known to be EBV-related which include (but are not limited to) gastric carcinoma (10-15%), lymphoma. These tumors (NPC excluded) should have:
- i)EBER in situ hybridisation on paraffin samples/ circulating tumor cells; or ii)Elevated pre-treatment serum EBV viral titres
- Patients who have had prior treatment with mTOR inhibitors and HDAC inhibitors will be allowed ONLY in the dose escalation phase
- Age ≥ 21 years old.
Key exclusion criteria (15 listed)
- Known brain metastases (locally advanced NPC with direct extension to central nervous system is permissible).
- Chemotherapy (in the case of nitrosoureas and mitomycin C within 6 weeks), radiotherapy, immunotherapy within 4 weeks before study drug administration.
- Patients receiving chronic immunosuppressive treatment with high dose corticosteroids (tailing doses or low doses are acceptable) or another immunosuppressive agent;
- Patients with uncontrolled diabetes (fasting glucose > 2x ULN);
- History of uncontrolled heart disease (unstable angina, congestive heart failure, myocardial infarction within preceding 12 months, clinically significant rhythm or conduction abnormality such as second and third degree heart block, congenital long QT syndrome, obligate use of a cardiac pacemaker. Patients with QTc at screening > 450 ms.
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 |
|---|---|---|
| LBH589 and RAD001Dose escalation of LBH589 tablets (5 and 10 mg) and RAD001 tablets (2.5, 5 mg and 10mg) | Drug | LBH589-RAD001 |
Primary outcome
Safety and tolerability
Time frame: Weekly evaluation for the first 5 weeks (DLT period), and continued follow up until patients come off trial due to toxicity or progressive disease
Patients will be followed closely for toxicities in the first cycle where they would have weekly consultations visit. After the first cycle, consultation visits will be once every 2 weeks or once a month depending on how well the patient is tolerating the treatment. The following safety assesments will be done on every visit; Vital signs and physical examination Haematology and blood chemistry Cardiac monitoring EBV DNA titre (for patients with EBV Driven tumors recording of adverse events and serious adverse events.
1 secondary outcome
Tumor response
Time frame: Every 2 months until disease progression or withdrawal from study - average of 6 - 12 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Apr 2018.
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.
Daniel Tan Shao Weng principal investigator
National Cancer Center Singapore
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 LBH589 and RAD001 in people with Nasopharyngeal Carcinoma, Lymphomas, Any EBV+ Solid Tumour, run by National Cancer Centre, Singapore at 1 site in Singapore.
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 15 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: status not confirmed, as of the sponsor's last update on 24 Apr 2018. 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 Singapore. 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?
Results are not available in the source record.
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 (time frame: Weekly evaluation for the first 5 weeks (DLT period), and continued follow up until patients come off trial due to toxicity or progressive disease). 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 Apr 2018.