LymphomaPhase 1/2NCT02091063
ACY-1215 for Relapsed/Refractory Lymphoid Malignancies
A Phase 1/2 study testing ACY-1215 in people with Lymphoma and Lymphoid Malignancies, run by Jennifer Amengual at 2 sites in United States.
Trial summary
This will be an open-label, single agent, multi-institutional phase Ib/II study of ACY-1215 for the treatment of patients with relapsed or refractory lymphoid malignancies. The target population will include patients with histologically confirmed relapsed or refractory non-Hodgkin's lymphoma or Hodgkin's lymphoma… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Lymphoma, Lymphoid Malignancies
- What is being tested?
- ACY-1215
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 23 participants
- Where
- 2 sitesUnited States
- Study dates
- 2 Apr 2014to 5 May 2019
- 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
- Patients must have histologically confirmed relapsed or refractory non-Hodgkin's lymphoma or Hodgkin's lymphoma (World Health Organization criteria), for which they are unwilling or unable to undergo an autologous stem cell transplant. Patients may have relapsed after prior stem cell transplant.
- Must have received first line chemotherapy. No upper limit to number of prior therapies.
- Patients must have measurable disease.
- Patients must be age ≥ 18.
- Patient has a Karnofsky Performance Status score of ≥70 or Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2
- The patient or the patient's legal representative is able to understand the risks of the study and provide signed informed consent and authorization to use protected health information (in accordance with national and local privacy regulations).
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- Patient has adequate bone marrow reserve, as evidenced by:
- Absolute neutrophil count (ANC) of ≥1.0x109/L.
- Platelet count of ≥50x109/L.
- Patient has adequate renal function, as evidenced by a creatinine within the institutional limits of normal or a calculated creatinine clearance of ≥30 mL/min according to the Cockcroft-Gault equation.
- Patient has adequate hepatic function, as evidenced by serum bilirubin values <2.0 mg/dL and serum alanine transaminase (ALT) and/or aspartate transaminase (AST) values <3 × the upper limit of normal (ULN) of the local laboratory reference range. (Patients with isolated elevations in alkaline phosphatase (ALP) <5 × ULN in the presence of bony disease are not excluded from participating in the study.)
- Females of childbearing potential must have a negative urine or serum pregnancy test within 7 days of (C1D1) and have adequate contraception. (A female is considered to be not of childbearing potential if she has undergone bilateral oophorectomy or if she has been menopausal without a menstrual period for 12 consecutive months.)
Who cannot join
- Prior Therapy
- Patients who have had chemotherapy or radiotherapy within 2 weeks of study drug treatment or those who have not recovered from adverse events due to agents administered
- Systemic steroids that have not been stabilized to the equivalent of ≤10 mg/day prednisone during the 7 days prior to the start of the study drugs.
- No monoclonal antibody within 3 months unless evidence of disease progression.
- Patients may not be receiving any other investigational agents.
- Patients with known central nervous system metastases, including lymphomatous meningitis
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- Any known cardiac abnormalities such as:
- Congenital long QT syndrome
- Corrected QT (QTc) interval ≥ 500 milliseconds;
- Uncontrolled inter-current illness
- Pregnant or nursing women
- Patient is known to be Human Immunodeficiency Virus (HIV)-positive
- Active Hepatitis A, Hepatitis B, or Hepatitis C infection
- Patient has a history of surgery that would interfere with the administration or absorption of the oral study drugs
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Columbia University Medical Center
New York, New York, 10019
Moffit Cancer Center
Tampa, Florida, 33612
About this study
Official title: A Study of the Selective HDAC6 Inhibitor, ACY-1215, for the Treatment of Patients With Relapsed or Refractory Lymphoid Malignancies
This will be an open-label, single agent, multi-institutional phase Ib/II study of ACY-1215 for the treatment of patients with relapsed or refractory lymphoid malignancies. The target population will include patients with histologically confirmed relapsed or refractory non-Hodgkin's lymphoma or Hodgkin's lymphoma, with an expansion cohort of patients with mantle cell lymphoma.
The phase Ib will be conducted to determine the safety and tolerability of two dosing schedules of ACY-1215 monotherapy in patients with lymphoid malignancies. Patients will be accrued simultaneously to two dose cohorts (Arm A and Arm B) of ACY-1215. Selection into each cohort will occur by alternation. All patients will take the prescribed dose of ACY-1215 orally for 28 consecutive days. Patients enrolled into Arm A will take ACY-1215 160 mg daily (QD), whereas patients enrolled into Arm B will take ACY-1215 160 mg twice daily (BID). ACY-1215 will be supplied as a liquid for oral administration (PO). Each dose will be administered at least 1 hour after ingestion of food followed by at least 4 ounces of water. Patients will be instructed not to ingest food or other oral medication for at least 2 hours after each ACY-1215 dose. Frequency in phase II will be determined based on Phase Ib results.
Read the detailed description
The emergence of epigenetic therapies has identified pan-class deacetylase (DAC) inhibitors as effective therapeutic agents for the treatment of lymphoma. While pan-class DAC inhibitors have led to FDA indications, clinical activity has been limited to the T-cell derived malignancies. The mechanism of action remains largely unknown and off-target effects lead to side effects including fatigue, gastrointestinal disturbances, and cytopenias. Recently, the development of isoform selective DAC inhibitors have opened the opportunity to investigate their mechanism. It is now recognized that DAC inhibitors not only have epigenetic properties, but have direct effects on transcription factors (p53), oncogenes (Bcl6), and protein degradation pathways (aggresome). Proteolysis occurs primarily through the ubiquitin-proteosome pathway. In states where this pathway is physiologically overwhelmed or therapeutically inhibited, the aggresome sequesters proteins for degradation. DAC6 is a class IIb deacetylase that facilitates misfolded protein transport to the aggresome for proteosome-independent proteolysis. Inhibition of the aggresome activates the unfolded protein response (UPR) pathway, a cellular quality control mechanism with two primary functions: (1) to promote survival during cellular endoplasmic reticulum (ER) stress by chaperoning proteins back for re-folding and halting further transcription until homeostasis is restored and (2) to signal CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) mediated apoptosis when homeostasis cannot be reestablished[9]. While most cells depend on both branches of the UPR to coordinate protein folding, lymphocytes physiologically down-regulate the UPR-apoptosis pathway, specifically CHOP, to allow for generation of high affinity antibodies. In addition to initiating genetic abnormalities (translocations and point mutations) lymphomas inherit this biology, and thus gain a survival advantage.
It has been shown ACY-1215, an Histone Deacetylase 6 (HDAC6)-selective, orally active small-molecule enzyme inhibitor has had single agent activity in a panel of lymphoma cell lines and mouse models, and marked synergistic activity with several agents such as bortezomib, carfilzomib, and ibrutinib, unpublished data. ACY-1215 has been studied in vivo in models of multiple myeloma and lymphoma with marked activity both as a single agent and in combination with bortezomib. Therefore ACY-1215 will be investigated for treatment of lymphoma as a single agent leading to future studies evaluating its effects in combination with other targeted agents known to be active in lymphoma and synergistic with ACY-1215.
- Conditions
- Lymphoma, Lymphoid Malignancies
- Being tested
- ACY-1215
- Keywords
- hematologic malignancies, hodgkin, hodgkins, non-hodgkin, non-hodgkins, mantle cell lymphoma, follicular, lymphoma, lymphoid malignancies
- Medical subject headings
- Lymphoma, Hematologic Neoplasms, Lymphoma, Mantle-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ACY-1215Drug
Also called Ricolinostat
All patients will take the oral ACY-1215 160mg for 28 consecutive days on a 28-day treatment cycle. Each dose will be administered at least 1 hour after ingestion of food and followed by at least 4 ounces of water. Patients will be instructed not to ingest food or other oral medication for at least 2 hours after each ACY-1215 dose.
| Study group | Role | What they receive |
|---|---|---|
| Phase Ib and II: ACY-1215 | Experimental | Participants will receive Phase Ib Arm A: ACY-1215 QD or Arm B: ACY-1215 BID. Once Phase I dosing schedule has been determined. 160 mg BID dosing will be administered for Phase II. Receives: Drug: ACY-1215 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Patients Who Experience a Dose-limiting Toxicity (DLT)
This is designed to establish the safety of 2 dose schedules of ACY-1215 in patients with relapsed or refractory lymphoid malignancies treated with ACY-1215. If more than 1/3 or 2/6 patients experience a DLT in Phase I, there will be no expansion.
Measured: Up to 1 year
Objective Response Rate
The anti-tumor activity of ACY-1215 will be measured by the number of subjects with the response rate in Phase II: complete response [CR] and partial response [PR].
Complete Response (CR) - Disappearance of all non-target lesions by PET/CT. Nodal Mass: (a) FDG-avid or PET positive prior to therapy; mass of any size permitted if PET negative or (b) Variably FDG-avid or PET negative; regression to normal size on CT. Spleen/Liver: Not palpable, nodules disappeared.
Partial Response (PR) - Regression of measurable disease and no new sites. Nodal Mass: 50% decrease in SPD of up to 6 largest dominant masses; no increase in size of other nodes, (a) FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site; (b) Variably FDG-avid or PET negative; regression on CT. Spleen/Liver: 50% decrease in SPD of nodules.
Measured: Up to 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Mar 2014 (estimated)
- Study start2 Apr 2014
- Primary completion25 Feb 2019
- Study completion5 May 2019
Why it stopped: Lack of funding
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 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
- Sequential
- Masking
- None (open label)
- Enrolment
- 23 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jennifer Amengual
- Sponsor type
- University, hospital or other
- Collaborators
- Acetylon Pharmaceuticals Incorporated
- Responsible party
- Sponsor-investigator, Jennifer Amengual, Columbia University
- Investigators
- Jennifer E Amengual, MD, Principal investigator, Columbia University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02091063
- Sponsor's protocol ID
- AAAM4054
- Status last verified
- Jul 2024
- First submitted
- 14 Mar 2014
- Last updated
- 6 Aug 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Study of the Selective HDAC6 Inhibitor, ACY-1215, for the Treatment of Patients With Relapsed or Refractory Lymphoid Malignancies
- ClinicalTrials.gov ID
- NCT02091063
- Acronym / sponsor ID
- AAAM4054
- Conditions
- Lymphoma, Lymphoid Malignancies
- Keywords
- hematologic malignancies, hodgkin, hodgkins, non-hodgkin, non-hodgkins, mantle cell lymphoma, follicular, lymphoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Lack of funding
- Enrolment
- 23 participants (actual)
- Lead sponsor
- Jennifer AmengualUniversity, hospital or other
- Collaborators
- Acetylon Pharmaceuticals Incorporated
- Study start
- 2 Apr 2014 (actual)
- Primary completion
- 25 Feb 2019 (actual)
- Study completion
- 5 May 2019 (actual)
- First posted
- 19 Mar 2014 (estimated)
- Results
- Posted 6 Aug 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This will be an open-label, single agent, multi-institutional phase Ib/II study of ACY-1215 for the treatment of patients with relapsed or refractory lymphoid malignancies. The target population will include patients with histologically confirmed relapsed or refractory non-Hodgkin's lymphoma or Hodgkin's lymphoma, with an expansion cohort of patients with mantle cell lymphoma.
The phase Ib will be conducted to determine the safety and tolerability of two dosing schedules of ACY-1215 monotherapy in patients with lymphoid malignancies. Patients will be accrued simultaneously to two dose cohorts (Arm A and Arm B) of ACY-1215. Selection into each cohort will occur by alternation. All patients will take the prescribed dose of ACY-1215 orally for 28 consecutive days. Patients enrolled into Arm A will take ACY-1215 160 mg daily (QD), whereas patients enrolled into Arm B will take ACY-1215 160 mg twice daily (BID). ACY-1215 will be supplied as a liquid for oral administration (PO). Each dose will be administered at least 1 hour after ingestion of food followed by at least 4 ounces of water. Patients will be instructed not to ingest food or other oral medication for at least 2 hours after each ACY-1215 dose. Frequency in phase II will be determined based on Phase Ib results.
Detailed description
The emergence of epigenetic therapies has identified pan-class deacetylase (DAC) inhibitors as effective therapeutic agents for the treatment of lymphoma. While pan-class DAC inhibitors have led to FDA indications, clinical activity has been limited to the T-cell derived malignancies. The mechanism of action remains largely unknown and off-target effects lead to side effects including fatigue, gastrointestinal disturbances, and cytopenias. Recently, the development of isoform selective DAC inhibitors have opened the opportunity to investigate their mechanism. It is now recognized that DAC inhibitors not only have epigenetic properties, but have direct effects on transcription factors (p53), oncogenes (Bcl6), and protein degradation pathways (aggresome). Proteolysis occurs primarily through the ubiquitin-proteosome pathway. In states where this pathway is physiologically overwhelmed or therapeutically inhibited, the aggresome sequesters proteins for degradation. DAC6 is a class IIb deacetylase that facilitates misfolded protein transport to the aggresome for proteosome-independent proteolysis. Inhibition of the aggresome activates the unfolded protein response (UPR) pathway, a cellular quality control mechanism with two primary functions: (1) to promote survival during cellular endoplasmic reticulum (ER) stress by chaperoning proteins back for re-folding and halting further transcription until homeostasis is restored and (2) to signal CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) mediated apoptosis when homeostasis cannot be reestablished[9]. While most cells depend on both branches of the UPR to coordinate protein folding, lymphocytes physiologically down-regulate the UPR-apoptosis pathway, specifically CHOP, to allow for generation of high affinity antibodies. In addition to initiating genetic abnormalities (translocations and point mutations) lymphomas inherit this biology, and thus gain a survival advantage.
It has been shown ACY-1215, an Histone Deacetylase 6 (HDAC6)-selective, orally active small-molecule enzyme inhibitor has had single agent activity in a panel of lymphoma cell lines and mouse models, and marked synergistic activity with several agents such as bortezomib, carfilzomib, and ibrutinib, unpublished data. ACY-1215 has been studied in vivo in models of multiple myeloma and lymphoma with marked activity both as a single agent and in combination with bortezomib. Therefore ACY-1215 will be investigated for treatment of lymphoma as a single agent leading to future studies evaluating its effects in combination with other targeted agents known to be active in lymphoma and synergistic with ACY-1215.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Phase Ib and II: ACY-1215 | Experimental | Drug: ACY-1215Participants will receive Phase Ib Arm A: ACY-1215 QD or Arm B: ACY-1215 BID. Once Phase I dosing schedule has been determined. 160 mg BID dosing will be administered for Phase II. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Patients must have histologically confirmed relapsed or refractory non-Hodgkin's lymphoma or Hodgkin's lymphoma (World Health Organization criteria), for which they are unwilling or unable to undergo an autologous stem cell transplant. Patients may have relapsed after prior stem cell transplant.
- Must have received first line chemotherapy. No upper limit to number of prior therapies.
- Patients must have measurable disease.
- Patients must be age ≥ 18.
- Patient has a Karnofsky Performance Status score of ≥70 or Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2
Key exclusion criteria (14 listed)
- Prior Therapy
- Patients may not be receiving any other investigational agents.
- Patients with known central nervous system metastases, including lymphomatous meningitis
- Any known cardiac abnormalities such as:
- Uncontrolled inter-current illness
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 |
|---|---|---|
| ACY-1215Also: RicolinostatAll patients will take the oral ACY-1215 160mg for 28 consecutive days on a 28-day treatment cycle. Each dose will be administered at least 1 hour after ingestion of food and followed by at least 4 ounces of water. Patients will be instructed not to ingest food or other oral medication for at least 2 hours after each ACY-1215 dose. | Drug | Phase Ib and II: ACY-1215 |
Primary outcome
Number of Patients Who Experience a Dose-limiting Toxicity (DLT)
Time frame: Up to 1 year
This is designed to establish the safety of 2 dose schedules of ACY-1215 in patients with relapsed or refractory lymphoid malignancies treated with ACY-1215. If more than 1/3 or 2/6 patients experience a DLT in Phase I, there will be no expansion.
Objective Response Rate
Time frame: Up to 3 years
The anti-tumor activity of ACY-1215 will be measured by the number of subjects with the response rate in Phase II: complete response [CR] and partial response [PR]. Complete Response (CR) - Disappearance of all non-target lesions by PET/CT. Nodal Mass: (a) FDG-avid or PET positive prior to therapy; mass of any size permitted if PET negative or (b) Variably FDG-avid or PET negative; regression to normal size on CT. Spleen/Liver: Not palpable, nodules disappeared. Partial Response (PR) - Regression of measurable disease and no new sites. Nodal Mass: 50% decrease in SPD of up to 6 largest dominant masses; no increase in size of other nodes, (a) FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site; (b) Variably FDG-avid or PET negative; regression on CT. Spleen/Liver: 50% decrease in SPD of nodules.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Aug 2024.
- 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.
Jennifer E Amengual, MD principal investigator
Columbia University
2 sites 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 ACY-1215 in people with Lymphoma and Lymphoid Malignancies, run by Jennifer Amengual 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 12 inclusion and 14 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: stopped early, as of the sponsor's last update on 6 Aug 2024. 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 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 6 Aug 2024). 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?
Number of Patients Who Experience a Dose-limiting Toxicity (DLT) (time frame: Up to 1 year). 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 6 Aug 2024.