Hodgkin's LymphomaPhase 1/2NCT00792467
Trial of the Histone-Deacetylase Inhibitor ITF2357 Followed by Mechlorethamine in Relapsed/Refractory Hodgkin's Lymphoma
A Phase 1/2 study testing ITF2357 in people with Hodgkin's Lymphoma, run by Italfarmaco at 1 site in Italy.
Trial summary
This study has the following objectives: Primary Objective To evaluate the anti-lymphoma efficacy of daily oral doses of ITF2357 followed by intravenous Mechlorethamine administered to patients with refractory/relapsed Hodgkin's lymphoma. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hodgkin's Lymphoma
- What is being tested?
- ITF2357
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteItaly
- Study dates
- Feb 2008to Sep 2010
- Phase
- Phase 1/2
- 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
- Written Informed Consent;
- Age ≥18 years;
- Histologically confirmed diagnosis of Hodgkin's lymphoma;
- Subjects who have failed second-line or subsequent-line salvage chemo- radiotherapy regimens for whom no other treatment options of proven efficacy can be given;
- Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements;
- ANC ≥1500/µL; Platelet count ≥75000/µL;
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- Hemoglobin ≥9 g/dL (may not be transfused or treated with erythropoietin to maintain or exceed this level);
- Total bilirubin ≤1.6 mg/dL; AST or ALT ≤2.5 times the upper limit of normal;
- Serum creatinine ≤2.0 mg/dL or creatinine clearance >50 mL/min;
- Serum Potassium and Magnesium within normal limits;
- Subjects with at least one bi-dimensional lesion measurable by CT-scan or MRI, according to the Revised Response Criteria for Malignant Lymphoma of the International Working Group (J Clin Oncol, 25:579-586, 2007);
- ECOG performance status of 0 or 1;
- Use of an effective means of contraception for women of childbearing potential and men with partners of childbearing potential;
- Life expectancy of >3 months;
- Subjects receiving intravenous Mechlorethamine (6 mg/sqm) as single agent at least 4 weeks before study entry;
- Willingness and capability to comply with the requirements of the study.
Who cannot join
- Active bacterial or mycotic infection requiring antimicrobial treatment
- Pregnancy or lactation
- Anticancer chemotherapy or radiotherapy during the study or within 4 weeks of study entry.
- A marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTc interval > 450 ms, according to Bazett's correction formula - see appendix I for the formula)
- Use of concomitant medications that prolong the QT/QTc interval (see appendix H for full list)
- Clinically significant cardiovascular disease including:
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- Uncontrolled hypertension, myocardial infarction, unstable angina
- New York Heart Association (NYHA) Grade II or greater congestive heart failure
- History of any cardiac arrhythmia requiring medication (irrespective of its severity)
- A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
- Positive blood test for HIV, HBV and HCV
- Identification of viral DNA by quantitative PCR for EBV and JC virus.
- History of other diseases, metabolic dysfunctions, physical examination findings, or clinical laboratory findings giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk from treatment complications
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase II Trial of the Histone-Deacetylase Inhibitor ITF2357 Followed by Mechlorethamine in Relapsed/Refractory Hodgkin's Lymphoma Patients
This study has the following objectives:
Primary Objective
- To evaluate the anti-lymphoma efficacy of daily oral doses of ITF2357 followed by intravenous Mechlorethamine administered to patients with refractory/relapsed Hodgkin's lymphoma.
Secondary Objective
- To evaluate the safety and tolerability of multiple courses of ITF2357 followed by Mechlorethamine in a population of chemotherapy pretreated patients.
Read the detailed description
This is a single-center, open label, phase II study aimed at testing the activity of multiple cycles of ITF2357 followed by Mechlorethamine administered to patients with relapsed/refractory Hodgkin's lymphoma.
Patients will receive a maximum of twelve 3-week cycles of ITF2357 followed by Mechlorethamine according to the following schema:
- ITF2357, 50 mg every 6 hours, per os, days 1 - 3
- Mechlorethamine, 6 mg/sqm, intravenously , day 4 Study therapy will be administered every 21 days as long as there is no evidence of progressive disease or unacceptable adverse events or patient's request to discontinue treatment occurs, but in any case for a maximum of 12 cycles.
Decision regarding the continuation of ITF2357/Mechlorethamine therapy will be made on (i)the basis of tumor reassessment following cycles 2, 6, 9, and 12 and (ii) the occurrence of toxicity. Tumor response will be evaluated according to the International Working Group response criteria HL.
Treatment will be administrated on an outpatient basis and patients will be followed regularly with physical and laboratory tests, as specified in the protocol; in case of hospitalisation, the treatment will be continued or interrupted according to the Investigators' decision.
The study will accrue 23 patients evaluable for efficacy and the anticipated duration of the study is about 24 months.
Histone deacetylases (HDACs) are enzymes involved in the remodeling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addition, the activity of non-histone proteins can be regulated through HDAC-mediated hypoacetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies.
Hodgkin's lymphoma (HL) is a relatively uncommon lymphoma histotype, with an incidence in Italy of approximately 1700 new cases per year (approximately 12% of all lymphomas). Combination chemotherapy with or without radiotherapy cures approximately 70 percent of advanced-stage HL. Fifty percent of the failing patients can be salvaged by second line chemotherapy (mainly high-dose regimens), while the remaining patients eventually die by disease progression. The development of an effective salvage regimen for this refractory/resistant population represents a true unmet medical need.
The use in the latter patient subset of HDAC inhibitors, like ITF2357, is supported by several considerations. Namely: (1) a related hydroxamate, SAHA, has shown activity in this clinical condition; (2) the drug markedly inhibits the production of several cytokines, and cytokine production in HL granuloma has a defined role in the pathogenesis of HL; (3) an effective treatment for refractory/relapsed HL is presently lacking; (4) ITF2357, up to 200 mg daily per os, has shown a favorable toxicity profile. All the above mentioned arguments represent a strong rationale prompting the use of ITF2357 in this patient population.
- Conditions
- Hodgkin's Lymphoma
- Being tested
- ITF2357
- Medical subject headings
- Hodgkin Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ITF2357Drug
Also called Givinostat, histone deacetylase inhibitor
ITF2357, supplied as hard gelatine capsules for oral administration at the strength of 50 mg each.
| Study group | Role | What they receive |
|---|---|---|
| ITF2357 | Experimental | Patients received the following therapy cycle
* ITF2357, 50 mg every 6 hours, per os, days 1 - 3;
* Mechlorethamine, 6 mg/sqm, intravenously , day 4. Therapy was administered every 21 days as long as there was no evidence of progressive disease or unacceptable toxicity, but in any case for a maximum of 12 cycles.
The mean number of complete treatment cycles received by patients was 5.25, with a minimum of 1 cycle and a maximum of 12 cycles. Receives: Drug: ITF2357 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective Response Rate (ORR)
OR rate among patients treated is defined according to the Revised Response Criteria for Malignant Lymphoma of the International Working Group.
In medicine, a response rate is the percentage of patients whose cancer shrinks or disappears after treatment.
The FDA definition of ORR is the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period.
The tumor objective response rate (ORR) is an important parameter to demonstrate the efficacy of a treatment in oncology.
The ORR is valuable for clinical decision making in routine practice and a significant end-point for reporting the results of clinical trials.
Measured: At each 21-day cycle for a maximum of 12 cycles
Proportion of Responders (Complete -CR- or Partial PR-)
Complete responder (CR) and partial responder (PR) among patients treated are defined according to the Revised Response Criteria for Malignant Lymphoma of the International Working Group.
CR is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy.
PR is defined as regression of measurable disease and no new sites. The frequencies of patients achieving objective response (i.e. subjects whose best overall response was CR or PR) and the frequencies of patients who did not achieve an objective response (i.e.subjects whose best overall response was equal to stable disease - SD, progressive disease - PD - or not evaluable) in ITT and PP populations are reported.
NED= no evidence of disease
Measured: At each 21-day cycle for a maximum of 12 cycles
Secondary outcomes (3)
Progression-Free Survival (PFS)
PFS is defined as the time from the 1st day of the 1st cycle of treatment until objective tumor progression or death. It included deaths, thus could be correlated to overall survival. If a patient did not have disease progression, PFS was censored at the date of last available tumor assessment (including those at end of study or follow-up visit).
Measured: From the first day of the first cycle of treatment until objective tumor progression or death, whichever came first, assessed up to 450 days from the start of the first cycle of treatment
Time To Response (TTR)
TTR is defined as the time from the 1st day of the 1st cycle until the date of achieving a response (CR or PR).
In case of no objective response, TTR was censored at the date of last available tumor assessment (including those at end of study or follow-up visit).
Measured: From the first day of the first cycle until the date of achieving a response assessed up to 250 days from the start of the first cycle of treatment
Response Duration (RD):
Duration of objective response (CR or PR) was applied only to patients whose best overall response was CR or PR.
Measured: From the first day of the first cycle of treatment until objective tumor progression or death, whichever came first, or last available tumor assessment (assessed up to 350 days from the start of the first cycle of treatment).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Nov 2008 (estimated)
- Study startFeb 2008
- Primary completionJul 2010
- Study completionSep 2010
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 Hodgkin's LymphomaStudies 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 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- Italfarmaco
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Alessandro Massimo Gianni, MD, Principal investigator, Istituto Nazionale per la Cura e lo Studio dei Tumori, Milano, Italy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00792467
- Sponsor's protocol ID
- DSC/07/2357/31
- Other IDs
- 2007-007091-41
- Status last verified
- Apr 2021
- First submitted
- 17 Nov 2008
- Last updated
- 11 May 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 11 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Trial of the Histone-Deacetylase Inhibitor ITF2357 Followed by Mechlorethamine in Relapsed/Refractory Hodgkin's Lymphoma Patients
- ClinicalTrials.gov ID
- NCT00792467
- Acronym / sponsor ID
- DSC/07/2357/31
- Conditions
- Hodgkin's Lymphoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- ItalfarmacoIndustry (pharma, biotech, devices)
- Study start
- Feb 2008
- Primary completion
- Jul 2010 (actual)
- Study completion
- Sep 2010 (actual)
- First posted
- 18 Nov 2008 (estimated)
- Results
- Posted 19 Apr 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study has the following objectives:
Primary Objective
- To evaluate the anti-lymphoma efficacy of daily oral doses of ITF2357 followed by intravenous Mechlorethamine administered to patients with refractory/relapsed Hodgkin's lymphoma.
Secondary Objective
- To evaluate the safety and tolerability of multiple courses of ITF2357 followed by Mechlorethamine in a population of chemotherapy pretreated patients.
Detailed description
This is a single-center, open label, phase II study aimed at testing the activity of multiple cycles of ITF2357 followed by Mechlorethamine administered to patients with relapsed/refractory Hodgkin's lymphoma.
Patients will receive a maximum of twelve 3-week cycles of ITF2357 followed by Mechlorethamine according to the following schema:
- ITF2357, 50 mg every 6 hours, per os, days 1 - 3
- Mechlorethamine, 6 mg/sqm, intravenously , day 4 Study therapy will be administered every 21 days as long as there is no evidence of progressive disease or unacceptable adverse events or patient's request to discontinue treatment occurs, but in any case for a maximum of 12 cycles.
Decision regarding the continuation of ITF2357/Mechlorethamine therapy will be made on (i)the basis of tumor reassessment following cycles 2, 6, 9, and 12 and (ii) the occurrence of toxicity. Tumor response will be evaluated according to the International Working Group response criteria HL.
Treatment will be administrated on an outpatient basis and patients will be followed regularly with physical and laboratory tests, as specified in the protocol; in case of hospitalisation, the treatment will be continued or interrupted according to the Investigators' decision.
The study will accrue 23 patients evaluable for efficacy and the anticipated duration of the study is about 24 months.
Histone deacetylases (HDACs) are enzymes involved in the remodeling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addition, the activity of non-histone proteins can be regulated through HDAC-mediated hypoacetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies.
Hodgkin's lymphoma (HL) is a relatively uncommon lymphoma histotype, with an incidence in Italy of approximately 1700 new cases per year (approximately 12% of all lymphomas). Combination chemotherapy with or without radiotherapy cures approximately 70 percent of advanced-stage HL. Fifty percent of the failing patients can be salvaged by second line chemotherapy (mainly high-dose regimens), while the remaining patients eventually die by disease progression. The development of an effective salvage regimen for this refractory/resistant population represents a true unmet medical need.
The use in the latter patient subset of HDAC inhibitors, like ITF2357, is supported by several considerations. Namely: (1) a related hydroxamate, SAHA, has shown activity in this clinical condition; (2) the drug markedly inhibits the production of several cytokines, and cytokine production in HL granuloma has a defined role in the pathogenesis of HL; (3) an effective treatment for refractory/relapsed HL is presently lacking; (4) ITF2357, up to 200 mg daily per os, has shown a favorable toxicity profile. All the above mentioned arguments represent a strong rationale prompting the use of ITF2357 in this patient population.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| ITF2357 | Experimental | Drug: ITF2357Patients received the following therapy cycle * ITF2357, 50 mg every 6 hours, per os, days 1 - 3; * Mechlorethamine, 6 mg/sqm, intravenously , day 4. Therapy was administered every 21 days as long as there was no evidence of progressive disease or unacceptable toxicity, but in any case for a maximum of 12 cycles. The mean number of complete treatment cycles received by patients was 5.25, with a minimum of 1 cycle and a maximum of 12 cycles. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- Written Informed Consent;
- Age ≥18 years;
- Histologically confirmed diagnosis of Hodgkin's lymphoma;
- Subjects who have failed second-line or subsequent-line salvage chemo- radiotherapy regimens for whom no other treatment options of proven efficacy can be given;
- Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements;
Key exclusion criteria (13 listed)
- Active bacterial or mycotic infection requiring antimicrobial treatment
- Pregnancy or lactation
- Anticancer chemotherapy or radiotherapy during the study or within 4 weeks of study entry.
- A marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTc interval > 450 ms, according to Bazett's correction formula - see appendix I for the formula)
- Use of concomitant medications that prolong the QT/QTc interval (see appendix H for full list)
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 |
|---|---|---|
| ITF2357Also: Givinostat, histone deacetylase inhibitorITF2357, supplied as hard gelatine capsules for oral administration at the strength of 50 mg each. | Drug | ITF2357 |
Primary outcome
Objective Response Rate (ORR)
Time frame: At each 21-day cycle for a maximum of 12 cycles
OR rate among patients treated is defined according to the Revised Response Criteria for Malignant Lymphoma of the International Working Group. In medicine, a response rate is the percentage of patients whose cancer shrinks or disappears after treatment. The FDA definition of ORR is the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period. The tumor objective response rate (ORR) is an important parameter to demonstrate the efficacy of a treatment in oncology. The ORR is valuable for clinical decision making in routine practice and a significant end-point for reporting the results of clinical trials.
Proportion of Responders (Complete -CR- or Partial PR-)
Time frame: At each 21-day cycle for a maximum of 12 cycles
Complete responder (CR) and partial responder (PR) among patients treated are defined according to the Revised Response Criteria for Malignant Lymphoma of the International Working Group. CR is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. PR is defined as regression of measurable disease and no new sites. The frequencies of patients achieving objective response (i.e. subjects whose best overall response was CR or PR) and the frequencies of patients who did not achieve an objective response (i.e.subjects whose best overall response was equal to stable disease - SD, progressive disease - PD - or not evaluable) in ITT and PP populations are reported. NED= no evidence of disease
3 secondary outcomes
Progression-Free Survival (PFS)
Time frame: From the first day of the first cycle of treatment until objective tumor progression or death, whichever came first, assessed up to 450 days from the start of the first cycle of treatment
Time To Response (TTR)
Time frame: From the first day of the first cycle until the date of achieving a response assessed up to 250 days from the start of the first cycle of treatment
Response Duration (RD):
Time frame: From the first day of the first cycle of treatment until objective tumor progression or death, whichever came first, or last available tumor assessment (assessed up to 350 days from the start of the first cycle of treatment).
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 May 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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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.
Alessandro Massimo Gianni, MD principal investigator
Istituto Nazionale per la Cura e lo Studio dei Tumori, Milano, Italy
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 ITF2357 in people with Hodgkin's Lymphoma, run by Italfarmaco at 1 site in Italy.
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 16 inclusion and 13 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 11 May 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 Italy. 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?
Yes. Results are posted in the registry (first posted 19 Apr 2021). 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?
Objective Response Rate (ORR) (time frame: At each 21-day cycle for a maximum of 12 cycles). 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 11 May 2021.