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

2022년 1월 4일 업데이트: 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.

연구 개요

상태

완전한

정황

개입 / 치료

상세 설명

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).

연구 유형

중재적

등록 (실제)

80

단계

  • 2 단계
  • 1단계

연락처 및 위치

이 섹션에서는 연구를 수행하는 사람들의 연락처 정보와 이 연구가 수행되는 장소에 대한 정보를 제공합니다.

연구 장소

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

참여기준

연구원은 적격성 기준이라는 특정 설명에 맞는 사람을 찾습니다. 이러한 기준의 몇 가지 예는 개인의 일반적인 건강 상태 또는 이전 치료입니다.

자격 기준

공부할 수 있는 나이

18년 이상 (성인, 고령자)

건강한 자원 봉사자를 받아들입니다

아니

연구 대상 성별

모두

설명

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.

공부 계획

이 섹션에서는 연구 설계 방법과 연구가 측정하는 내용을 포함하여 연구 계획에 대한 세부 정보를 제공합니다.

연구는 어떻게 설계됩니까?

디자인 세부사항

  • 주 목적: 치료
  • 할당: 해당 없음
  • 중재 모델: 단일 그룹 할당
  • 마스킹: 없음(오픈 라벨)

무기와 개입

참가자 그룹 / 팔
개입 / 치료
실험적: 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
의약품: panobinostat
Specified dose on specified days
다른 이름들:
  • LBH589 (Panobinostat)
의약품: carfilzomib
Specified dose on specified days
다른 이름들:
  • PX-171-007

연구는 무엇을 측정합니까?

주요 결과 측정

결과 측정
측정값 설명
기간
Number of Phase I Patients (Dose Level 1-6) Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Optimal Dosage
기간: 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
기간: 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

2차 결과 측정

결과 측정
측정값 설명
기간
Time-to-progression (TTP)
기간: 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)
기간: 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)
기간: up to 6 years
Measured from time of first study treatment until date of death or date last known alive.
up to 6 years

공동 작업자 및 조사자

여기에서 이 연구와 관련된 사람과 조직을 찾을 수 있습니다.

스폰서

SCRI Development Innovations, LLC

협력자

Novartis
Onyx Therapeutics, Inc.

간행물 및 유용한 링크

연구에 대한 정보 입력을 담당하는 사람이 자발적으로 이러한 간행물을 제공합니다. 이것은 연구와 관련된 모든 것에 관한 것일 수 있습니다.

일반 간행물

연구 기록 날짜

이 날짜는 ClinicalTrials.gov에 대한 연구 기록 및 요약 결과 제출의 진행 상황을 추적합니다. 연구 기록 및 보고된 결과는 공개 웹사이트에 게시되기 전에 특정 품질 관리 기준을 충족하는지 확인하기 위해 국립 의학 도서관(NLM)에서 검토합니다.

연구 주요 날짜

연구 시작

2011년 12월 1일

기본 완료 (실제)

2020년 12월 1일

연구 완료 (실제)

2020년 12월 1일

연구 등록 날짜

최초 제출

2011년 12월 15일

QC 기준을 충족하는 최초 제출

2011년 12월 20일

처음 게시됨 (추정)

2011년 12월 21일

연구 기록 업데이트

마지막 업데이트 게시됨 (실제)

2022년 2월 2일

QC 기준을 충족하는 마지막 업데이트 제출

2022년 1월 4일

마지막으로 확인됨

2022년 1월 1일

추가 정보

이 연구와 관련된 용어

키워드

추가 관련 MeSH 약관

기타 연구 ID 번호

  • SCRI MM 27

이 정보는 변경 없이 clinicaltrials.gov 웹사이트에서 직접 가져온 것입니다. 귀하의 연구 세부 정보를 변경, 제거 또는 업데이트하도록 요청하는 경우 register@clinicaltrials.gov. 문의하십시오. 변경 사항이 clinicaltrials.gov에 구현되는 즉시 저희 웹사이트에도 자동으로 업데이트됩니다. .

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