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Multiple MyelomaPhase 1/2NCT02057640

MLN9708 (Ixazomib) in Combination With Panobinostat and Dexamethasone in Multiple Myeloma

A Phase 1/2 study testing Panobinostat, Dexamethasone and MLN9708 in people with Multiple Myeloma and Kahler Disease, run by Jason Valent at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This study will look at the safety and tolerability of the new drug MLN9708 in combination with the existing drugs panobinostat and dexamethasone among patients with relapsed or refractory multiple myeloma. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Panobinostat, Dexamethasone and MLN9708
Could I receive a placebo?
No, everyone receives an active treatment
How many people
16 participants
Where
2 sitesUnited States
Study dates
22 May 2014to 15 May 2018
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

  • Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
  • Patients must carry a diagnosis of symptomatic multiple myeloma according to international myeloma working group criteria and have relapsed or refractory disease according to international uniform response criteria and must have previously received therapy with a proteasome inhibitor and an IMiD™
  • Must have measurable disease defined as any of the following: Serum m-spike ≥ 1g/dL, 24 h urine m-spike of at least 200mg/d, involved serum free light chains ≥ 100mg/L with abnormal serum free light chain ratio, bone marrow plasma cells of at least 30%
  • ECOG PS ≤ 2
  • No gastro-intestinal condition, that in the opinion of the treating physician or the principal investigator significantly limits oral absorption
  • No serious uncontrolled coexisting medical condition
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  • Patients must meet the following laboratory criteria:
  • ANC ≥ 1.0 x 10^9/L without use of pegfilgrastim in the preceding 21 days and without non-pegylated G-CSF or GM-CSF within 7 days prior to study entry
  • Hemoglobin ≥ 8 g/dl (may be after transfusion of packed red blood cells or use of erythropoiesis stimulating agents)
  • Platelets ≥ 70x 10^9/L without platelet transfusion 7 days prior to study entry
  • AST and ALT ≤ 2.5 x ULN
  • Serum bilirubin ≤ 1.5 x ULN
  • Serum potassium ≥ LLN and serum magnesium ≥ LLN (electrolyte levels may be achieved with repletion or other supportive medications like potassium sparing diuretics)
  • Creatinine clearance ≥ 30 mL/min according to Cockroft-Gault formula
  • Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.
  • Baseline MUGA or ECHO must demonstrate LVEF ≥ 45%
  • Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to start of study treatment
  • Male patients, even if surgically sterilized (i.e., status post vasectomy), have to either:
  • Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study treatment, 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 [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.
  • Female patients have to fulfill one of the following:
  • Be postmenopausal for at least 1 year before the Screening visit, OR
  • Be surgically sterile, OR
  • If of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study treatment
  • Oral contraceptives are generally metabolized by CYP3A4. Since the induction potential of panobinostat to induce CYP3A4 is unknown, patients who are using oral contraceptives as a method of contraception, and are sexually active, should use another effective contraceptive method, 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 [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
  • At least 7 days must have passed since the last treatment with lenalidomide, pomalidomide, thalidomide, proteasome inhibitors, or low dose cyclophosphamide (up to 50mg daily), at least 21 days must have passed since the last treatment with daratumumab, elotuzumab, investigational therapy and most conventional chemotherapy including cyclophosphamide above 50mg per dose, bendamustine, doxorubicin, cisplatin, and etoposide; and at least 35 days since the last treatment with melphalan.

Who cannot join

  • Prior anti-cancer treatment with MLN9708 (ixazomib), HDAC, DAC, HSP90 inhibitors or valproic acid
  • Prior participation in a randomized controlled study that included MLN9708 (ixazomib) in one of the treatment arms independent of whether assigned to MLN9708 (ixazomib) or not
  • Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment
  • Female patients who are lactating or have a positive serum pregnancy test during the screening period.
  • Impaired cardiac function or clinically significant cardiac diseases, including any one of the following:
  • History or presence of sustained ventricular tachyarrhythmia. (Patients with a history of atrial arrhythmia are eligible)
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  • Any history of ventricular fibrillation or torsade de pointes
  • Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if HR ≥ 50 bpm.
  • Screening ECG with a QTcF > 470 msec (QTcF=QT/3√RR). If potassium or magnesium blood levels are below normal limits, consider repeating ECG after correction of these electrolytes
  • Right bundle branch block + left anterior hemiblock (bifascicular block)
  • Patients with myocardial infarction or unstable angina ≤ 6 months prior to starting study drug
  • Other clinically significant heart disease (e.g., CHF NY Heart Association class III or IV , uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
  • Impairment of GI function or GI disease that may significantly alter the swallowing absorption of panobinostat and MLN9708
  • Patients with diarrhea > CTCAE (version 4.03) grade 2
  • Patient has ≥ Grade 3 peripheral neuropathy, or ≥ Grade 2 with pain on clinical examination during the screening period.
  • Patients with known metastasis of malignant plasma cells to the central nervous system (if not suspected nonspecific testing is required)
  • Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol
  • Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug. If an alternative medication that does not risk QT prolongation can safely be used in the opinion of the treating physician and the treatment is changed to that medication, the patient may be enrolled.
  • Patients who have not passed the nadir of bone marrow suppression from previous anti-myeloma therapy yet. If in doubt, serial CBCs with differential should be obtained.
  • The corticosteroids prednisone and dexamethasone may be continued until the day before treatment start if all related adverse events are controlled at CTCAE version 4.03 grade ≤ 1.
  • Patients who have received radiation therapy to more than half of the pelvis or more than half of the spine within ≤ 2 weeks prior to starting study treatment; or who have not yet recovered from side effects of such therapies.
  • Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
  • Systemic treatment, within 14 days before study enrollment, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.
  • Ongoing or active systemic infection, known human immunodeficiency virus (HIV) positive, known active hepatitis B virus hepatitis, or known active hepatitis C virus hepatitis.
  • Concurrent diagnosis of another malignancy if either systemic treatment or surgery is expected to be required within 2 years from study entry.
  • Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
  • Patients with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff.
  • Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment unless the patient is felt to have fully recovered and any antibiotics that are continued are either beta lactam antibiotics or are specifically allowed on study.
  • 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.

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • University Hospitals Cleveland Medical Center, Seidman Cancer Center, Case Comprehensive Cancer Center

    Cleveland, Ohio, 44106

  • Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

    Cleveland, Ohio, 44195

Other trials in United States

About this study

Official title: A Phase I/II Study of MLN9708 (Ixazomib) in Combination With Panobinostat and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

This study will look at the safety and tolerability of the new drug MLN9708 in combination with the existing drugs panobinostat and dexamethasone among patients with relapsed or refractory multiple myeloma. This study will also look at the response and clinical benefit of the treatment and the progression-free survival and overall survival of study participants.

Read the detailed description

The primary objective of this study is to define the tolerability and safety of MLN9708 (ixazomib) administered on a day 1,8,15 every 28 day schedule up to 4mg in combination with fixed doses of panobinostat and dexamethasone in patients with relapsed or refractory myeloma.

The secondary objectives of this study are to assess response and clinical benefit response rates according to international uniform response criteria and adapted EBMT criteria, respectively. And to assess progression-free survival (PFS) and overall survival (OS).

Being tested
Panobinostat, Dexamethasone, MLN9708
Medical subject headings
Multiple Myeloma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PanobinostatDrug

    20mg, on day 1, 3, 5, 15, 17, 19, 28

  • DexamethasoneDrug

    20mg, on day 1, 2, 8, 9, 15, 16, 28

  • MLN9708Drug

    Also called Ixazomib

    4mg on day 1, 8, 15, 28

Study groups in NCT02057640
Study groupRoleWhat they receive
Combination therapy: Panobinostat, dexamethasone, MLN9708ExperimentalPanobinostat: 20mg, on day 1, 3, 5, 15, 17, 19, 28 Dexamethasone: 20mg, on day 1, 2, 8, 9, 15, 16, 28 MLN9708: 4mg on day 1, 8, 15, 28
Receives: Drug: Panobinostat; Drug: Dexamethasone; Drug: MLN9708

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With Dose Limiting Toxicity According to CTCAE Version 4.03

    Number of Participants with Dose Limiting Toxicity of MLN9708 (lxazomib) according to CTCAE version 4.03

    Measured: at 28 days from start of treatment

Secondary outcomes (3)

  1. Response to Combination Therapy (Panobinostat, Dexamethasone, MLN9708)

    Response to intervention as measured by international uniform response criteria and clinical benefit response according to modified EBMT response criteria, comparing myeloma panels obtained at the beginning of each cycle that include SPEP, 24 h UPEP, serum and urine IFEs, and serum free light chains to results at screening. In addition a baseline bone marrow exam and skeletal survey will be obtained and repeated as clinically indicated and for assessment of complete remission (bone marrow)

    Measured: 4 months (102 days)

  2. Progression-free Survival

    Progression-free survival will be the number of days from study entry to progression or death of any cause, whichever comes first.

    Progression-free survival is survival with absence of progressive disease, defined by

    • An increase of 25% from lowest response value in any one or more of the following:
    • Serum M-component (absolute increase must be >0.5 g/100 ml) *
    • Urine M-component (absolute increase must be >200mg per 24 h)
    • Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be >100 mg/l)
    • Bone marrow plasma cell percentage (absolute % must be >10%)
    • And / or:
    • Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas
    • Development of hypercalcemia (corrected serum calcium >11.5 mg/100 ml) that can be attributed solely to the plasma cell proliferative disorder

    Measured: 1 year from start of treatment

  3. Overall Survival

    Overall survival for all will be the number of months from study entry to death from any cause.

    Measured: up to 3 years from start of treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Feb 2014 (estimated)
  2. Study start22 May 2014
  3. Primary completion15 May 2018
  4. Study completion15 May 2018

Resources

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
16 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02057640
Sponsor's protocol ID
CASE4A13
Status last verified
Dec 2019
First submitted
6 Feb 2014
Last updated
11 Dec 2019
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Panobinostat, Dexamethasone and MLN9708 in people with Multiple Myeloma and Kahler Disease, run by Jason Valent 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 28 inclusion and 29 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 Dec 2019. 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 11 Dec 2019). 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 Participants With Dose Limiting Toxicity According to CTCAE Version 4.03 (time frame: at 28 days from start of treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02057640.

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 Dec 2019.

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