Multiple MyelomaPhase 1NCT02468687
NMP in Relapsed / Refractory Myeloma
A Phase 1 study testing N-methyl-pyrrolidone in people with Multiple Myeloma, run by Peter MacCallum Cancer Centre, Australia at 1 site in Australia.
Trial summary
The study will evaluate if the N-methyl-pyrrolidone (NMP) can be safely administered to humans at doses, which induce measurable immunological and anti-tumour effects in patients with myeloma who are resistant to or intolerant of lenalidomide and bortezomib. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Multiple Myeloma
- What is being tested?
- N-methyl-pyrrolidone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 13 participants
- Where
- 1 siteAustralia
- Study dates
- 20 Aug 2015to 7 Oct 2021
- 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed diagnosis of plasma cell myeloma defined by WHO 2008 criteria
- Measurable disease as defined by at least one of:
- serum M protein ≥5g/L
- urine M protein ≥ 200mg/24hrs
- involved serum free light chain ≥ 100mg/L
- measurable (by imaging at the discretion of the investigator) soft tissue plasmacytoma
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- Relapsed, refractory or intolerant of both bortezomib and lenalidomide
- Definitions:
- refractory at least 4 weeks of therapy administered, with less than a partial response by IMWG criteria
- relapsed from previous response (PR or greater) to therapy, with subsequent disease progression as defined as development of bone marrow dysfunction (fall in Hb of 20g/L or platelet count <100 x 109/L) due to increased bone marrow plasmacytosis
- OR new lytic bone lesions
- OR increase in serum M protein of 5g/L
- OR absolute increase of involved serum free light chain of >250mg/L
- intolerant: grade 2 or higher toxicity unresponsive to dose adjustment 4. Prior autologous stem cell transplant, unless ineligible for transplant by the discretion of the investigator.
- 5. age ≥18 years 6. ECOG performance status <2 7. The following values within 7 days of commencing NMP (blood transfusions prior to study entry are permitted)
- Haemoglobin >80g/L
- Absolute neutrophil count >1.0 x 109/L
- Platelet count ≥ 25 x 109/L
- Creatinine clearance >30ml/min (by Cockcroft/Gault)
- Bilirubin ≤ 3x upper limit of normal (ULN)
- ALT ≤ 3 x ULN
- Left ventricular ejection fraction (LVEF) ≥45% (by gated cardiac blood pool scan or echocardiography) 9. Life expectancy > 3 months 10. Able to give written informed consent 11. In the opinion of the investigator, willing and able to comply with required study procedures 12. Able to take oral medications (no malabsorptive condition)
Who cannot join
- Pregnant or breastfeeding female patients
- Female of child bearing potential unwilling or unable to use two methods of contraception
- Received chemotherapy, immunotherapy or biological therapy within two weeks of enrolment. Prednisolone up to 20mg per day permitted for non-myeloma indications.
- Patients with a history of another malignancy within 2 years of the baseline visit, excluding treated non-melanotic skin cancer and in-situ carcinoma.
- Patients with known CNS involvement unless previously treated and well controlled for a period of ≥3 months AND which do not require the use of steroids.
- Uncontrolled intercurrent illness including, but not limited to:
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- Active or uncontrolled infection, including active HIV or viral (A, B or C) hepatitis. NOTE: Patients with controlled infection on antibiotic or antifungal therapy are eligible i.e. the patient should be afebrile for at least 72 hours and be haemodynamically stable.
- Impaired cardiac function, including any of the following:
- Myocardial infarction within previous 3 months prior to starting study
- Symptomatic congestive heart failure (New York Heart Association Class III, IV)
- Symptomatic coronary artery disease
- Cardiac arrhythmia not controlled by medication
- Clinically significant resting bradycardia (<50 beats per minute)
- Long QT syndrome or a known family history of long QT syndrome or QTc > 450 msec on baseline ECG (using the QTcF formula). If QTcF >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc
- Inability to monitor the QT/QTc interval on ECG
- Other clinically significant uncontrolled heart disease (e.g. unstable angina or uncontrolled hypertension)
- Impaired hepatic or renal impairment (see inclusion criteria)
- Uncontrolled diarrhoea, nausea or vomiting
- concomitant exposure to another investigational agent
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Phase I, Open Label Dose Escalation Trial of Orally Administered N-methyl-pyrrolidone (NMP) in Patients With Relapsed or Refractory Myeloma
The study will evaluate if the N-methyl-pyrrolidone (NMP) can be safely administered to humans at doses, which induce measurable immunological and anti-tumour effects in patients with myeloma who are resistant to or intolerant of lenalidomide and bortezomib.
Read the detailed description
N-Methyl-2-pyrrolidone (NMP) is a small molecule acetyl-lysine mimetic compound with potent (low micromolar range) immunomodulatory and direct anti-myeloma activity attributable to BETbromodomain inhibition at higher concentrations. NMP is nontoxic, stable and already in use as a solvent in biomedical applications. It has been the subject of numerous toxicity studies in humans and been demonstrated to have few adverse effects. The study is proposing an empiric starting dose of 50mg daily, 50% of that seen in healthy volunteers with no observable toxicity. Dose escalation will follow a rule based on accelerated trial design in order to minimise the number of patients treated at sub-therapeutic doses and minimise the length of the study. During the accelerated dose-escalation phase, one patient will be entered per cohort with a dose escalation increment of 100%, with up to 6 dose escalation and up to two dose de-escalation levels.The accelerated phase ends when one patient experiences DLT during the first cycle of treatment or when a total of two patients have experienced moderate toxicity during the first cycle of treatment regardless of the dose level; or the most recent patient has been treated at the highest dose level in the first cycle. If 1 patient experiences a DLT in the first cycle at any dose level, the cohort will be further expanded to a total of 6 patients treated at the same dose level. The maximum tolerated dose (MTD) in the study will be defined as the highest dose in which the incidence of DLT was less than 33%.
- Conditions
- Multiple Myeloma
- Being tested
- N-methyl-pyrrolidone
- Keywords
- Relapsed/Refractory
- Medical subject headings
- Multiple Myeloma, Recurrence
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
N-methyl-pyrrolidoneDrug
Also called NMP
NMP will be taken each morning as a single daily dose of oral suspension at a concentration of 50mg/ml on an empty stomach at least 30 minutes prior to food.
| Study group | Role | What they receive |
|---|---|---|
| N-methyl-pyrrolidone | Other | NMP dose escalation in accelerated phase and standard phase Receives: Drug: N-methyl-pyrrolidone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Adverse events to establish the Maximum Tolerated Dose (MTD)
Each patient will be monitored for adverse events during the first cycle of NMP treatment (28 days) to establish the maximum tolerated dose
Measured: 28 days
Secondary outcomes (5)
Optimum biological dose (OBD)
The maximum changes in correlative biomarkers will be tested at the specific time-points. Descriptive statistics will be used to analyse data from correlative studies and summarized in graphical or tabular formats as appropriate.
Measured: 6 months
Safety of the repeated dosing of NMP by oral administration - possible toxicities
To assess safety, the numbers and rates (with confidence intervals) of patients experiencing any haematological and non-haematological and specific grade 3+ adverse events experienced at each given dose level and schedule of NMP will be calculated, over the full treatment period and by cycle
Measured: 6 months
Pharmacokinetic properties of NMP after oral administration
Pick plasma concentrations (Cmax) of NMP
Measured: Predose,0.5,1,2,4,8, 24 hours post dose
Response rate measured using IMWG criteria
Patients will be evaluated for response after every 28 day cycle for the first 6 cycles of treatment and thereafter every 2 months in follow up using the IMWG criteria for multiple myeloma.
Measured: 6 months up to 2 years
Time to progression from start of treatment
Patients will be assessed for disease progression weekly in Cycle 1, then monthly on D1 of each cycle during treatment for the first 6 months and then monthly until disease progression, next anti-cancer treatment or death. Time to progression from start of treatment will be estimated using Kaplan Meier survival curves.
Measured: up to 3.5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jun 2015 (estimated)
- Study start20 Aug 2015
- Primary completion7 Oct 2021
- Study completion7 Oct 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Multiple MyelomaStudies 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
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- Peter MacCallum Cancer Centre, Australia
- Sponsor type
- University, hospital or other
- Collaborators
- Melbourne Health
- Responsible party
- Sponsor
- Investigators
- David Ritchie, Prof, Principal investigator, Melbourne Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02468687
- Sponsor's protocol ID
- HREC/14/MH/159
- Status last verified
- May 2022
- First submitted
- 2 Jun 2015
- Last updated
- 5 May 2022
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 5 May 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I, Open Label Dose Escalation Trial of Orally Administered N-methyl-pyrrolidone (NMP) in Patients With Relapsed or Refractory Myeloma
- ClinicalTrials.gov ID
- NCT02468687
- Acronym / sponsor ID
- HREC/14/MH/159
- Conditions
- Multiple Myeloma
- Keywords
- Relapsed/Refractory
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 13 participants (actual)
- Lead sponsor
- Peter MacCallum Cancer Centre, AustraliaUniversity, hospital or other
- Collaborators
- Melbourne Health
- Study start
- 20 Aug 2015 (actual)
- Primary completion
- 7 Oct 2021 (actual)
- Study completion
- 7 Oct 2021 (actual)
- First posted
- 11 Jun 2015 (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 study will evaluate if the N-methyl-pyrrolidone (NMP) can be safely administered to humans at doses, which induce measurable immunological and anti-tumour effects in patients with myeloma who are resistant to or intolerant of lenalidomide and bortezomib.
Detailed description
N-Methyl-2-pyrrolidone (NMP) is a small molecule acetyl-lysine mimetic compound with potent (low micromolar range) immunomodulatory and direct anti-myeloma activity attributable to BETbromodomain inhibition at higher concentrations. NMP is nontoxic, stable and already in use as a solvent in biomedical applications. It has been the subject of numerous toxicity studies in humans and been demonstrated to have few adverse effects. The study is proposing an empiric starting dose of 50mg daily, 50% of that seen in healthy volunteers with no observable toxicity. Dose escalation will follow a rule based on accelerated trial design in order to minimise the number of patients treated at sub-therapeutic doses and minimise the length of the study. During the accelerated dose-escalation phase, one patient will be entered per cohort with a dose escalation increment of 100%, with up to 6 dose escalation and up to two dose de-escalation levels.The accelerated phase ends when one patient experiences DLT during the first cycle of treatment or when a total of two patients have experienced moderate toxicity during the first cycle of treatment regardless of the dose level; or the most recent patient has been treated at the highest dose level in the first cycle. If 1 patient experiences a DLT in the first cycle at any dose level, the cohort will be further expanded to a total of 6 patients treated at the same dose level. The maximum tolerated dose (MTD) in the study will be defined as the highest dose in which the incidence of DLT was less than 33%.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| N-methyl-pyrrolidone | Other | Drug: N-methyl-pyrrolidoneNMP dose escalation in accelerated phase and standard phase |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (22 listed)
- Histologically confirmed diagnosis of plasma cell myeloma defined by WHO 2008 criteria
- Measurable disease as defined by at least one of:
- Relapsed, refractory or intolerant of both bortezomib and lenalidomide
- refractory at least 4 weeks of therapy administered, with less than a partial response by IMWG criteria
- relapsed from previous response (PR or greater) to therapy, with subsequent disease progression as defined as development of bone marrow dysfunction (fall in Hb of 20g/L or platelet count <100 x 109/L) due to increased bone marrow plasmacytosis
Key exclusion criteria (19 listed)
- Pregnant or breastfeeding female patients
- Female of child bearing potential unwilling or unable to use two methods of contraception
- Received chemotherapy, immunotherapy or biological therapy within two weeks of enrolment. Prednisolone up to 20mg per day permitted for non-myeloma indications.
- Patients with a history of another malignancy within 2 years of the baseline visit, excluding treated non-melanotic skin cancer and in-situ carcinoma.
- Patients with known CNS involvement unless previously treated and well controlled for a period of ≥3 months AND which do not require the use of steroids.
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 |
|---|---|---|
| N-methyl-pyrrolidoneAlso: NMPNMP will be taken each morning as a single daily dose of oral suspension at a concentration of 50mg/ml on an empty stomach at least 30 minutes prior to food. | Drug | N-methyl-pyrrolidone |
Primary outcome
Adverse events to establish the Maximum Tolerated Dose (MTD)
Time frame: 28 days
Each patient will be monitored for adverse events during the first cycle of NMP treatment (28 days) to establish the maximum tolerated dose
5 secondary outcomes
Optimum biological dose (OBD)
Time frame: 6 months
Safety of the repeated dosing of NMP by oral administration - possible toxicities
Time frame: 6 months
Pharmacokinetic properties of NMP after oral administration
Time frame: Predose,0.5,1,2,4,8, 24 hours post dose
Response rate measured using IMWG criteria
Time frame: 6 months up to 2 years
Time to progression from start of treatment
Time frame: up to 3.5 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 May 2022.
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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.
David Ritchie, Prof principal investigator
Melbourne Health
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 N-methyl-pyrrolidone in people with Multiple Myeloma, run by Peter MacCallum Cancer Centre, Australia at 1 site in Australia.
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 22 inclusion and 19 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 5 May 2022. 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 Australia. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Adverse events to establish the Maximum Tolerated Dose (MTD) (time frame: 28 days). 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 5 May 2022.