Tato stránka byla automaticky přeložena a přesnost překladu není zaručena. Podívejte se prosím na anglická verze pro zdrojový text.

Study of the Combination of Panobinostat and Carfilzomib in Patients With Relapsed/Refractory Multiple Myeloma

4. ledna 2022 aktualizováno: SCRI Development Innovations, LLC

Phase I/II Study of the Combination of Panobinostat and Carfilzomib in Patients With Relapsed/Refractory Multiple Myeloma

Relapsed/refractory Multiple Myeloma (MM) is an incurable disorder with a poor prognosis. Carfilzomib is a novel proteasome inhibitor with activity in this setting. Panobinostat is a pan-deacetylase inhibitor which has shown synergistic cytotoxicity in vitro and in vivo with proteasome inhibitors. The combination should enhance the activity of both agents against myeloma cells. In Phase I, the optimal doses of the combination of carfilzomib and panobinostat will be determined. Assuming this combination is feasible, the Phase II portion will proceed using the doses determined in Phase I.

Přehled studie

Postavení

Dokončeno

Podmínky

Intervence / Léčba

Detailní popis

In this open-label, non-randomized Phase I/II study, a maximum of 4 planned dose levels of carfilzomib and panobinostat were evaluated to determine the maximum tolerated dose (MTD) to administer. The MTD was not reached so patients in Phase II received treatment at dose level 4 to further assess efficacy. Response to treatment was evaluated after each 4-week cycle. Those having an objective response or stable disease are continuing treatment until disease progression or unacceptable toxicity occurs.

As the MTD in the 4 planned dose levels were not reached, a parallel Phase I study was initiated to examine additional dose levels using a traditional 3+3 design. If these dose levels are tolerable, then more patients will be recruited into an expansion cohort to assess efficacy at the new dose level(s).

Typ studie

Intervenční

Zápis (Aktuální)

80

Fáze

  • Fáze 2
  • Fáze 1

Kontakty a umístění

Tato část poskytuje kontaktní údaje pro ty, kteří studii provádějí, a informace o tom, kde se tato studie provádí.

Studijní místa

  • Spojené státy
    • Colorado
      • Denver, Colorado, Spojené státy, 80218
        • Colorado Blood Cancer Institute
    • Florida
      • Fort Myers, Florida, Spojené státy, 33916
        • Florida Cancer Specialists South
      • Pensacola, Florida, Spojené státy, 32503
        • Woodlands Medical Specialists
      • Saint Petersburg, Florida, Spojené státy, 33705
        • Florida Cancer Specialists North
    • Indiana
      • Terre Haute, Indiana, Spojené státy, 47802
        • Providence Medical Group
      • Terre Haute, Indiana, Spojené státy, 47802
        • RHHP/Hope Cancer Center
    • Missouri
      • Kansas City, Missouri, Spojené státy, 64132
        • Research Medical Center
    • New Jersey
      • Morristown, New Jersey, Spojené státy, 07962
        • Hematology-Oncology Associates - Northern NJ
    • Ohio
      • Cincinnati, Ohio, Spojené státy, 45242
        • Oncology Hematology Care, Inc.
    • Oklahoma
      • Lawton, Oklahoma, Spojené státy, 73505
        • Cancer Centers of Southwest Oklahoma
    • Tennessee
      • Chattanooga, Tennessee, Spojené státy, 37404
        • Tennessee Oncology-Chattanooga
      • Nashville, Tennessee, Spojené státy, 37205
        • Tennessee Oncology
    • Texas
      • Fort Worth, Texas, Spojené státy, 76104
        • The Center for Cancer and Blood Disorders

Kritéria účasti

Výzkumníci hledají lidi, kteří odpovídají určitému popisu, kterému se říká kritéria způsobilosti. Některé příklady těchto kritérií jsou celkový zdravotní stav osoby nebo předchozí léčba.

Kritéria způsobilosti

Věk způsobilý ke studiu

18 let a starší (Dospělý, Starší dospělý)

Přijímá zdravé dobrovolníky

Ne

Pohlaví způsobilá ke studiu

Všechno

Popis

Inclusion Criteria:

  1. Eligible participants must have multiple myeloma using standard criteria.

  2. Patients must have measurable disease requiring systemic therapy defined as at least one of the following:

    • Serum M-protein ≥1 g/dl (≥10 g/l)
    • Urine M-protein ≥200 mg/24 hrs
    • Serum free light chain assay: involved free light chain level ≥10 mg/dl (≥100 mg/l) provided the serum free light chain ratio is abnormal
  3. Must have progressed during or after at least one previous bortezomib-containing treatment regimen. Patients who have received previous high-dose therapy/autologous stem cell transplantation are eligible.
  4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

  5. Must meet the following laboratory criteria:

    • Absolute neutrophil count (ANC) ≥1000/μL;
    • Platelets ≥70,000/microL;
    • AST or ALT and alkaline phosphatase (ALP) must be ≤ 2.5 x ULN, or ≤ 5 x ULN in patients with plasmacytomas of the liver;
    • Total bilirubin ≤ 1.5 x the institutional ULN;
    • Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 ml/min;
    • Serum potassium, calcium, magnesium WNL (These may be corrected prior to starting therapy, to make the patient eligible.)
  6. Ability to swallow oral medications.
  7. Baseline MUGA or ECHO must demonstrate left ventricular ejection fraction (LVEF) ≥ the lower limit of the institutional limits of normal.
  8. Male or females ≥ 18 years of age.
  9. Female patients must not be of child-bearing potential or must agree to use adequate contraceptive measures.
  10. Male patients willing to use adequate contraceptive measures.
  11. Willingness and ability to comply with the trial and follow-up procedures.
  12. Ability to understand the nature of this trial and give written informed consent.

Exclusion Criteria:

  1. Currently receiving or have received systemic cancer therapy (chemotherapy, biologic therapy) ≤ 21 days of initiating study therapy. For patients receiving small molecule targeted therapy, study treatment may begin >21 days after last dose or >5 half lives of previous treatment, whichever is shorter. Patients must have completed radiation therapy ≥7 days prior to starting study treatment. Patients must have recovered from or come to a new chronic stable baseline from all treatment-related toxicities. Dexamethasone or other high-dose steroid therapy must be stopped ≥ days prior to starting study treatment.
  2. Previous treatment with HDAC, DAC, HSP90 or valproic acid for treatment of cancer.
  3. Requires valproic acid for any medical condition during the study ≤5 days prior to first panobinostat treatment.
  4. Patient has not recovered from all therapy-related toxicities associated with prior treatments to < Grade 2 CTCAE.
  5. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).
  6. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis ≤14 days prior to study entry.
  7. Patients using medications that have a risk of prolonging the QT interval or inducing Torsade de Pointes if treatment cannot be discontinued or switched to a different medication prior to receiving study drug.
  8. Patients with > grade 2 diarrhea.
  9. Patients with impaired cardiac function.
  10. Infection requiring IV antibiotics.
  11. Patients with > grade 2 peripheral neuropathy or with uncontrolled pain.
  12. Women who are pregnant or lactating.
  13. Any concurrent medical illness that may impair the ability of the patient to tolerate study treatment and comply with the requirements of the study.
  14. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.
  15. Use of any non-approved or investigational agent ≤30 days prior to administration of the first dose of study drug. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.
  16. Presence of other active cancers, or history of treatment for invasive cancer ≤ 5 years. Patients with stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e. non-invasive) are eligible, as are patients with history of non-melanoma skin cancer.

Studijní plán

Tato část poskytuje podrobnosti o studijním plánu, včetně toho, jak je studie navržena a co studie měří.

Jak je studie koncipována?

Detaily designu

  • Primární účel: Léčba
  • Přidělení: N/A
  • Intervenční model: Přiřazení jedné skupiny
  • Maskování: Žádné (otevřený štítek)

Zbraně a zásahy

Skupina účastníků / Arm
Intervence / Léčba
Experimentální: Carfilzomib and Panobinostat

Phase I:

Carfilzomib: cycle 1 - Dose is 20 mg/m^2 IV on day 1; 27 or 36 or 45 or 56 mg/m^2 IV on Days 8, 9, 15, 16 cycle 2 to progression - 27 or 36 or 45 or 56 mg/m^2 IV on days 1, 2, 8, 9, 15, 16

Panobinostat: cycle 1 and cycle 2 to progression - 20 mg or 30 mg on days 1, 3, 5, 15, 17, 19

Phase II:

Carfilzomib and Panobinostat: Dose is optimal dose determined in Phase I
Lék: panobinostat
Specified dose on specified days
Ostatní jména:
  • LBH589 (Panobinostat)
Lék: carfilzomib
Specified dose on specified days
Ostatní jména:
  • PX-171-007

Co je měření studie?

Primární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Number of Phase I Patients (Dose Level 1-6) Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Optimal Dosage
Časové okno: 28 days from the start of study treatment

Using a traditional 3+3 dose escalation design, successive cohorts of subjects will receive a fixed dose level of the drug combination. The MTD is defined as the highest dose level at which ≤1 of 6 subjects experiences a dose-limiting toxicity (DLT) assessed by NCI CTCAE v4.0. DLT is defined as any of the following that are determined to be related to study treatment during Cycle 1:

Grade 4 neutropenia for >7 days, Febrile neutropenia, Grade 3 thrombocytopenia with ≥ Grade 2 bleeding, Grade 4 thrombocytopenia > 7 days, ≥ Grade 2 neuropathy with uncontrolled pain, ≥ Grade 3 non-hematologic drug-related toxicity (excluding alopecia), despite optimal supportive care lasting >72 hours or requiring a dose reduction in the first cycle and Patients who are unable to receive 75% of the required doses of both agents secondary to toxicity. Number of Participants With such Dose Limiting Toxicities (DLT) at each level are reported here.
28 days from the start of study treatment
Phase II: Overall Response Rate
Časové okno: up to 6 years
Defined as the percentage of patients with confirmed complete response, very good partial response, or partial response (CR, VGPR, or PR) according to International Myeloma Working Group Uniform Response Criteria. CR=bone marrow contains ≤5% plasma cells; negative fixation on serum and urine; disappearance of soft tissue plasmacytomas. VGPR=≥90% reduction from baseline serum; urine M-protein level 100mg for 24h. PR=≥50% reduction from baseline in serum M-protein; disappearance of any soft tissue plasmacytomas.
up to 6 years

Sekundární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Time-to-progression (TTP)
Časové okno: up to 6 years
Measured from date of first treatment until date of first documented progression as per International Myeloma Working Group Uniform Response Criteria. Progressive disease id defined as an increase of ≥ 25% from the nadir in at least one of the following criteria: serum M-protein (absolute increase must be ≥0.5 g/dL); urine M-protein (absolute increase must be ≥200 mg/24h) ; only in patients with non-measurable serum and urine M-protein levels: difference in involved and uninvolved FLC levels (absolute increase must be >10 mg/dL); only in patients with non-measurable serum and urine M-protein levels and non-measurable disease by FLC levels, bone marrow plasma cell percentage (absolute % must be ≥10%) 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 OR Development of hypercalcemia (corrected serum Ca >11.5mg/dL) for patients without hypercalcemia at baseline
up to 6 years
Progression-free-survival (PFS)
Časové okno: up to 6 years
Measured from date of first protocol treatment until date of tumor progression or death as per International Myeloma Working Group Uniform Response Criteria. Progressive disease id defined as an increase of ≥ 25% from the nadir in at least one of the following criteria: serum M-protein (absolute increase must be ≥0.5 g/dL); urine M-protein (absolute increase must be ≥200 mg/24h) ; only in patients with non-measurable serum and urine M-protein levels: difference in involved and uninvolved FLC levels (absolute increase must be >10 mg/dL); only in patients with non-measurable serum and urine M-protein levels and non-measurable disease by FLC levels, bone marrow plasma cell percentage (absolute % must be ≥10%) 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 OR Development of hypercalcemia (corrected serum Ca >11.5mg/dL) for patients without hypercalcemia at baseline
up to 6 years
Overall-survival (OS)
Časové okno: up to 6 years
Measured from time of first study treatment until date of death or date last known alive.
up to 6 years

Spolupracovníci a vyšetřovatelé

Zde najdete lidi a organizace zapojené do této studie.

Sponzor

SCRI Development Innovations, LLC

Spolupracovníci

Novartis
Onyx Therapeutics, Inc.

Publikace a užitečné odkazy

Osoba odpovědná za zadávání informací o studiu tyto publikace poskytuje dobrovolně. Mohou se týkat čehokoli, co souvisí se studiem.

Obecné publikace

Termíny studijních záznamů

Tato data sledují průběh záznamů studie a předkládání souhrnných výsledků na ClinicalTrials.gov. Záznamy ze studií a hlášené výsledky jsou před zveřejněním na veřejné webové stránce přezkoumány Národní lékařskou knihovnou (NLM), aby se ujistily, že splňují specifické standardy kontroly kvality.

Hlavní termíny studia

Začátek studia

1. prosince 2011

Primární dokončení (Aktuální)

1. prosince 2020

Dokončení studie (Aktuální)

1. prosince 2020

Termíny zápisu do studia

První předloženo

15. prosince 2011

První předloženo, které splnilo kritéria kontroly kvality

20. prosince 2011

První zveřejněno (Odhad)

21. prosince 2011

Aktualizace studijních záznamů

Poslední zveřejněná aktualizace (Aktuální)

2. února 2022

Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality

4. ledna 2022

Naposledy ověřeno

1. ledna 2022

Více informací

Termíny související s touto studií

Klíčová slova

Další relevantní podmínky MeSH

Další identifikační čísla studie

  • SCRI MM 27

Tyto informace byly beze změn načteny přímo z webu clinicaltrials.gov. Máte-li jakékoli požadavky na změnu, odstranění nebo aktualizaci podrobností studie, kontaktujte prosím register@clinicaltrials.gov. Jakmile bude změna implementována na clinicaltrials.gov, bude automaticky aktualizována i na našem webu .

Předplatit