NeoplasmsPhase 1NCT03422874
Dose Escalation Study of Nelfinavir Plus MLN9708 in Patients With Advanced Solid Tumors or Lymphoma
A Phase 1 study testing MLN9708 and Nelfinavir in people with Neoplasms and Lymphoma, run by Dartmouth-Hitchcock Medical Center at 1 site in United States.
Trial summary
This is an open label, dose escalation, phase I study of the combination of MLN9708 plus Nelfinavir. Read more about this study
- Who is it for?
- Ages 18 years and older
- What is being tested?
- MLN9708 and Nelfinavir
- 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
- Aug 2016to 4 Aug 2017
- 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
- Advanced or metastatic, histologically/cytologically confirmed malignant solid tumor or any lymphoma, not expected to clinically benefit from standard therapy.
- Life expectancy greater than 3 months.
- Previous chemotherapy and/or radiotherapy must have been completed at least four weeks before enrollment(six weeks for prior treatment with mitomycin or nitrosoureas) and patients should have recovered from all toxicities of that therapy before treatment under this protocol.
- All patients must have recovered from any surgical procedure.
- Serum creatinine must be within the institutional limits of normal and an estimated creatinine clearance of ≥ 60 mL/min.
- Calculated by: Weight (in kg) X (140 - age) / (72 X Serum Creatinine)
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- In females, multiply by 0.85. Alternatively, creatinine clearance may be measured from a 24 hour urine collection.
- Total bilirubin <2 x ULN. SGOT/AST and ALT must be less than or equal to 2.5 times the upper limit of institutional normal.
- Hb > 9.0 g/dL and absolute neutrophil count ≥ 1,500/mm3, and platelet count ≥ 100,000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.
- Patients must be 18 years of age or older.
- Patients must have a Karnofsky Performance Status of >70%
- Female patients who:
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, AND
- Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
- Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, sympto-thermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
- Male patients who:
- Even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following:
- Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
- Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
- Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, sympto-thermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
- Brain metastases must be treated and stable for at least 3 months before the start of the treatment
- Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
Who cannot join
- Inability or unwillingness to swallow capsules.
- Patients with active hepatitis B or C.
- Patients with known HIV infection.
- Ongoing or active systemic infection.
- Evidence of current uncontrolled cardiovascular conditions including, but not limited to uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
- Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
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- Pregnant or lactating female patients.
- Patients with malabsorption syndromes, or who have undergone a resection or bypass of the distal stomach/ pylorus, or small bowel.
- Participation in other clinical trials, including those with other investigational agents not included in this trial, within 21 days of the start of this trial and throughout the duration of this trial.
- Use of strong CYP 3A4 or P-gp inhibitors and/or inducers.
- Use of strong CYP 1A2 inhibitors and/or inducers.
- See Table of prohibited drugs (Appendix G).
- Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.
- Failure to have fully recovered (i.e., < Grade 1 toxicity) from the reversible effects of prior chemotherapy.
- Major surgery within 14 days before enrollment.
- Radiotherapy within four weeks before enrollment. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the MLN9708.
- Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
- Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
- Patient has > Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period.
Trial locations and contacts
1 site in 1 country.
United States1 site
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, 03756
About this study
Official title: A Phase I Dose Escalation Study of Nelfinavir Plus MLN9708 in Patients With Advanced Solid Tumors or Lymphoma
This is an open label, dose escalation, phase I study of the combination of MLN9708 plus Nelfinavir.
Read the detailed description
This is an open label, dose escalation, phase I study of the combination of MLN9708 MLN9708 plus Nelfinavir. It will use a 3+3 cohort design to determine the maximum tolerated dose of the combination, which will be defined as the highest dose cohort where < 1/6 patients develop a dose limiting toxicity. The maximum tolerated dose cohort will be expanded to have at least 6 patients with biopsiable tumors who undergo pretreatment and post treatment tumor biopsies for molecular pharmacodynamic markers.
- Being tested
- MLN9708, Nelfinavir
- Keywords
- Advanced Solid Tumors, Lymphoma, Nelfinavir, MLN9708, proteasome inhibitor
- Medical subject headings
- Neoplasms, Lymphoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MLN9708Drug
Also called Ixazomib
MLN9708 is a second-generation reversible proteasome inhibitor which shows greater oral bioavailability, improved pharmacokinetics and enhanced antitumor activity compared with bortezomib (VELCADE®).
NelfinavirDrug
Also called Viracept
Nelfinavir is an oral HIV protease inhibitor approved by FDA in 1997, now available in generic form. It has a well established safety profile in HIV patients when administered at the recommended dose of 1250 mg PO BID. Nelfinavir was shown to induce ER stress in cancer cell lines and xenograft tumors leading to apoptosis and tumor growth inhibition.
| Study group | Role | What they receive |
|---|---|---|
| Nelfinavir plus MLN9708 | Experimental | Both Nelfinavir and MLN9708 will be given orally (by mouth). MLN9708 will be given as 3 mg orally twice weekly. Study drugs will be administered on 21-day treatment cycles. All cycles are 21 days.
During the first cycle of MLN9708 only will initially be administered orally at a fixed dose of 3mg twice weekly for 2 weeks, on Mondays and Thursdays during this treatment cycle. During the third week there will be no study combination drug therapy(for Cycle 1 only). During Cycles 2 and 3, MLN9708 administered twice weekly on Mondays and Thursdays for the first 2 weeks of Cycles 2 and 3. Nelfinavir (escalating cohorts [1250mg, 1875mg, 2500mg, 3125mg]) will be administered orally twice daily in the dose cohorts listed. Receives: Drug: MLN9708; Drug: Nelfinavir |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose (MTD) of nelfinavir
If 0/3 patients experience dose limiting toxicity, 3 patients will be treated at the next dose level. If dose limiting toxicity attributable to the study drug(s) is experienced in exactly 1/3 patients, 3 more patients (for a total of 6) will be treated at that dose level. If no additional dose limiting toxicity is observed at the expanded dose level (i.e. 1/6 with dose limiting toxicity), the dose will be escalated. Escalation will terminate as soon as two or more patients experience any dose limiting toxicity attributable to the study drug(s), at a given dose level. If 2 or more dose limiting toxicities are observed in any cohort, no further escalation will take place, and the Maximum Tolerated Dose will have been exceeded.
Measured: Approximately 1 year to establish MTD
The toxicity of MLN9708 when combined with nelfinavir based on CTCAE grading criteria v. 4.0
The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by NCI Revised Common Toxicity Criteria and nadir or maximum values for the laboratory measures), time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course.
Measured: Approximately 18-24 months to observe toxicity
Secondary outcomes (4)
Pharmacokinetics of both MLN9708 and nelfinavir based on parameters estimated using WinNonLin
MLN2238 concentrations-time data will be plotted on a semi-logarithmic plot and the decay of the drug concentrations over time inspected. The data will initially be analyzed using a non-compartmental and the primary pharmacokinetic parameters estimated using WinNonLin.
Measured: The study as a whole is estimated to be completed in 18-24 months.
Pharmacodynamics of MLN9708 based on peripheral blood mononuclear cells (PBMCs)
To explore the effect of nelfinavir on the pharmacodynamics of MLN9708 (as assessed by β1 and β5 inhibition in peripheral blood mononuclear cells (PBMCs), ATF-3, CHOP and GADD34 up-regulation in PBMCs.
Measured: The study as a whole is estimated to be completed in 18-24 months.
Pharmacodynamics of MLN9708 based on tumor tissue
To explore the effect of nelfinavir on the pharmacodynamics of MLN9708 based on tumor tissue apoptosis induction as detected by TUNEL stain, and activated caspase-3 cleavage in primary tumors.
Measured: The study as a whole is estimated to be completed in 18-24 months.
The anti-tumor activity of the MLN9708/Nelfinavir
Disease assessments, including radiological imagining will occur initially after 9 weeks of therapy and then every 6 weeks thereafter.
Measured: The study as a whole is estimated to be completed in 18-24 months.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Feb 2018
- Study startAug 2016
- Primary completion4 Aug 2017 (estimated)
- Study completion4 Aug 2017 (estimated)
Why it stopped: Sponsor withdrew support
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for NeoplasmsStudies of the same condition, open and under way.
- More trials run by Dartmouth-Hitchcock Medical CenterThe 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
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Dartmouth-Hitchcock Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Lionel D Lewis, MD, Principal investigator, Dartmouth-Hitchcock Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03422874
- Sponsor's protocol ID
- D14037
- Status last verified
- Jan 2018
- First submitted
- 31 Aug 2015
- Last updated
- 6 Feb 2018
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 6 Feb 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Dose Escalation Study of Nelfinavir Plus MLN9708 in Patients With Advanced Solid Tumors or Lymphoma
- ClinicalTrials.gov ID
- NCT03422874
- Acronym / sponsor ID
- D14037
- Keywords
- Advanced Solid Tumors, Lymphoma, Nelfinavir, MLN9708, proteasome inhibitor
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Sponsor withdrew support
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Dartmouth-Hitchcock Medical CenterUniversity, hospital or other
- Study start
- Aug 2016
- Primary completion
- 4 Aug 2017 (estimated)
- Study completion
- 4 Aug 2017 (estimated)
- First posted
- 6 Feb 2018 (actual)
- 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.
This is an open label, dose escalation, phase I study of the combination of MLN9708 plus Nelfinavir.
Detailed description
This is an open label, dose escalation, phase I study of the combination of MLN9708 MLN9708 plus Nelfinavir. It will use a 3+3 cohort design to determine the maximum tolerated dose of the combination, which will be defined as the highest dose cohort where < 1/6 patients develop a dose limiting toxicity. The maximum tolerated dose cohort will be expanded to have at least 6 patients with biopsiable tumors who undergo pretreatment and post treatment tumor biopsies for molecular pharmacodynamic markers.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Nelfinavir plus MLN9708 | Experimental | Drug: MLN9708, Drug: NelfinavirBoth Nelfinavir and MLN9708 will be given orally (by mouth). MLN9708 will be given as 3 mg orally twice weekly. Study drugs will be administered on 21-day treatment cycles. All cycles are 21 days. During the first cycle of MLN9708 only will initially be administered orally at a fixed dose of 3mg twice weekly for 2 weeks, on Mondays and Thursdays during this treatment cycle. During the third week there will be no study combination drug therapy(for Cycle 1 only). During Cycles 2 and 3, MLN9708 administered twice weekly on Mondays and Thursdays for the first 2 weeks of Cycles 2 and 3. Nelfinavir (escalating cohorts [1250mg, 1875mg, 2500mg, 3125mg]) will be administered orally twice daily in the dose cohorts listed. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (24 listed)
- Advanced or metastatic, histologically/cytologically confirmed malignant solid tumor or any lymphoma, not expected to clinically benefit from standard therapy.
- Life expectancy greater than 3 months.
- Previous chemotherapy and/or radiotherapy must have been completed at least four weeks before enrollment(six weeks for prior treatment with mitomycin or nitrosoureas) and patients should have recovered from all toxicities of that therapy before treatment under this protocol.
- All patients must have recovered from any surgical procedure.
- Serum creatinine must be within the institutional limits of normal and an estimated creatinine clearance of ≥ 60 mL/min.
Key exclusion criteria (19 listed)
- Inability or unwillingness to swallow capsules.
- Patients with active hepatitis B or C.
- Patients with known HIV infection.
- Ongoing or active systemic infection.
- Evidence of current uncontrolled cardiovascular conditions including, but not limited to uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
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 |
|---|---|---|
| MLN9708Also: IxazomibMLN9708 is a second-generation reversible proteasome inhibitor which shows greater oral bioavailability, improved pharmacokinetics and enhanced antitumor activity compared with bortezomib (VELCADE®). | Drug | Nelfinavir plus MLN9708 |
| NelfinavirAlso: ViraceptNelfinavir is an oral HIV protease inhibitor approved by FDA in 1997, now available in generic form. It has a well established safety profile in HIV patients when administered at the recommended dose of 1250 mg PO BID. Nelfinavir was shown to induce ER stress in cancer cell lines and xenograft tumors leading to apoptosis and tumor growth inhibition. | Drug | Nelfinavir plus MLN9708 |
Primary outcome
Maximum Tolerated Dose (MTD) of nelfinavir
Time frame: Approximately 1 year to establish MTD
If 0/3 patients experience dose limiting toxicity, 3 patients will be treated at the next dose level. If dose limiting toxicity attributable to the study drug(s) is experienced in exactly 1/3 patients, 3 more patients (for a total of 6) will be treated at that dose level. If no additional dose limiting toxicity is observed at the expanded dose level (i.e. 1/6 with dose limiting toxicity), the dose will be escalated. Escalation will terminate as soon as two or more patients experience any dose limiting toxicity attributable to the study drug(s), at a given dose level. If 2 or more dose limiting toxicities are observed in any cohort, no further escalation will take place, and the Maximum Tolerated Dose will have been exceeded.
The toxicity of MLN9708 when combined with nelfinavir based on CTCAE grading criteria v. 4.0
Time frame: Approximately 18-24 months to observe toxicity
The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by NCI Revised Common Toxicity Criteria and nadir or maximum values for the laboratory measures), time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course.
4 secondary outcomes
Pharmacokinetics of both MLN9708 and nelfinavir based on parameters estimated using WinNonLin
Time frame: The study as a whole is estimated to be completed in 18-24 months.
Pharmacodynamics of MLN9708 based on peripheral blood mononuclear cells (PBMCs)
Time frame: The study as a whole is estimated to be completed in 18-24 months.
Pharmacodynamics of MLN9708 based on tumor tissue
Time frame: The study as a whole is estimated to be completed in 18-24 months.
The anti-tumor activity of the MLN9708/Nelfinavir
Time frame: The study as a whole is estimated to be completed in 18-24 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 6 Feb 2018.
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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.
Lionel D Lewis, MD principal investigator
Dartmouth-Hitchcock Medical Center
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 MLN9708 and Nelfinavir in people with Neoplasms and Lymphoma, run by Dartmouth-Hitchcock Medical Center 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 24 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: withdrawn, as of the sponsor's last update on 6 Feb 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 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 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 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?
Maximum Tolerated Dose (MTD) of nelfinavir (time frame: Approximately 1 year to establish MTD). 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 Feb 2018.