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Olaparib and High-Dose Chemotherapy in Treating Patients With Relapsed or Refractory Lymphomas Undergoing Stem Cell Transplant

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03259503
Recruitment Status : Recruiting
First Posted : August 23, 2017
Last Update Posted : November 19, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE August 22, 2017
First Posted Date  ICMJE August 23, 2017
Last Update Posted Date November 19, 2019
Actual Study Start Date  ICMJE September 13, 2019
Estimated Primary Completion Date July 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 5, 2019)
Dose limiting toxicities (DLT) [ Time Frame: Up to 30 days ]
All adverse events will be tabulated by dose, and a Bayesian DLT curve will be fit.
Original Primary Outcome Measures  ICMJE
 (submitted: August 22, 2017)
Maximum Tolerated Dose (MTD) of Olaparib Combined with High-Dose Chemotherapy for Refractory Lymphomas [ Time Frame: 30 days after stem cell transplant ]
MTD determined by dose limiting toxicity (DLT) defined as grade 4 or 5 extra-medullary toxicity or non-infectious toxicity, or grade 3,4 mucositis lasting > 5 days at peak level. CTC version 4.0 criteria used to determine toxicities.
Change History Complete list of historical versions of study NCT03259503 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2019)
  • Overall survival (OS) [ Time Frame: At 2 years ]
    OS will be estimated by the method of Kaplan and Meier. Participants without an event at the analysis time point (2 years) will be censored.
  • Event-free survival (EFS) [ Time Frame: At 2 years ]
    EFS will be estimated by the method of Kaplan and Meier. Patients without an event at the analysis time point (2 years) will be censored. EFS is the time to relapse, secondary hematological malignancy, death, whichever occurred first, or last follow-up.
  • Objective response (OR) [ Time Frame: Up to 100 days ]
    OR will be tabulated by dose, and a Bayesian DLT curve will be fit.
  • Complete response (CR) [ Time Frame: At 100 days ]
    CR will be tabulated by dose, and a Bayesian DLT curve will be fit.
  • Incidence of adverse events [ Time Frame: At 2 years ]
    All adverse events will be tabulated by dose, and a Bayesian DLT curve will be fit.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 22, 2017)
  • Overall Survival (OS) of Olaparib Combined with High-Dose Chemotherapy for Refractory Lymphomas [ Time Frame: 2 years post auto-SCT ]
    OS estimated by the method of Kaplan and Meier.
  • Event Free Survival (EFS) of Olaparib Combined with High-Dose Chemotherapy for Refractory Lymphomas [ Time Frame: 2 years post auto-SCT ]
    EFS estimated by the method of Kaplan and Meier.
  • Complete Remission (CR) Rate of Olaparib Combined with High-Dose Chemotherapy for Refractory Lymphomas [ Time Frame: 100 days post auto-SCT ]
    CR tabulated by dose, and a Bayesian dose-DLT curve will be fit.
  • Overall Remission Rate (ORR) of Olaparib Combined with High-Dose Chemotherapy for Refractory Lymphomas [ Time Frame: 100 days post auto-SCT ]
    ORR tabulated by dose, and a Bayesian dose-DLT curve will be fit.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Olaparib and High-Dose Chemotherapy in Treating Patients With Relapsed or Refractory Lymphomas Undergoing Stem Cell Transplant
Official Title  ICMJE Olaparib Combined With High-Dose Chemotherapy for Refractory Lymphomas
Brief Summary This phase I trial studies the side effects and best dose of olaparib when given together with high-dose chemotherapy in treating patients with lymphomas that have come back or does not treatment and are undergoing stem cell transplant. Drugs used in chemotherapy, such as olaparib, vorinostat, gemcitabine, busulfan, and melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as rituximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving olaparib and high-dose chemotherapy together may work better in treating patients with relapsed/refractory lymphomas undergoing stem cell transplant than with chemotherapy alone.
Detailed Description

PRIMARY OBJECTIVE:

I. Establish the maximum tolerated dose (MTD) of olaparib combined with vorinostat/gemcitabine/busulfan/melphalan with autologous stem-cell transplant [ASCT]).

SECONDARY OBJECTIVES:

I. Determine the 2-year event-free survival (EFS). II. 2-year overall survival (OS). III. Complete remission (CR) rate. IV. Overall remission rate (ORR). V. Describe the toxicity profile. VI. Describe changes of deoxyribonucleic acid (DNA) damage response and repair, poly(ADP-ribose) polymerase (PARP) inhibition and downstream cellular effects in peripheral blood mononuclear cells and, when available, malignant lymphocytes obtained by fine needle aspiration (FNA) of peripheral lymph nodes.

OUTLINE: This is a dose-escalation study of olaparib.

Patients receive olaparib orally (PO) twice daily (BID) on days -11 to -3, vorinostat PO on days -10 to -3, gemcitabine intravenously (IV) over 4.5 hours on days -9 and -4, busulfan IV over 3 hours on day -9 to -6, melphalan IV over 30 minutes on days -4 and -3, and undergo peripheral blood stem cell transplant IV over 30-60 minutes on day 0. Patients with CD20+ tumors also receive rituximab IV over 3-6 hours on day -10.

After completion of study treatment, patients are followed up every 1-2 days for 30 days and then every 2 weeks for up to 100 days.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Recurrent Diffuse Large B-Cell Lymphoma
  • Recurrent T-Cell Non-Hodgkin Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma
  • Refractory Hodgkin Lymphoma
  • Refractory T-Cell Non-Hodgkin Lymphoma
Intervention  ICMJE
  • Drug: Busulfan
    Given IV
    Other Names:
    • 1, 4-Bis[methanesulfonoxy]butane
    • BUS
    • Bussulfam
    • Busulfanum
    • Busulfex
    • Busulphan
    • CB 2041
    • CB-2041
    • Glyzophrol
    • GT 41
    • GT-41
    • Joacamine
    • Methanesulfonic Acid Tetramethylene Ester
    • Methanesulfonic acid, tetramethylene ester
    • Mielucin
    • Misulban
    • Misulfan
    • Mitosan
    • Myeleukon
    • Myeloleukon
    • Myelosan
    • Mylecytan
    • Myleran
    • Sulfabutin
    • Tetramethylene Bis(methanesulfonate)
    • Tetramethylene bis[methanesulfonate]
    • WR-19508
  • Drug: Gemcitabine
    Given IV
    Other Names:
    • dFdC
    • dFdCyd
    • Difluorodeoxycytidine
  • Drug: Melphalan
    Given IV
    Other Names:
    • Alanine Nitrogen Mustard
    • CB-3025
    • L-PAM
    • L-Phenylalanine Mustard
    • L-sarcolysin
    • L-Sarcolysin Phenylalanine mustard
    • L-Sarcolysine
    • Melphalanum
    • Phenylalanine Mustard
    • Phenylalanine nitrogen mustard
    • Sarcoclorin
    • Sarkolysin
    • WR-19813
  • Drug: Olaparib
    Given PO
    Other Names:
    • AZD 2281
    • AZD-2281
    • AZD2281
    • KU-0059436
    • Lynparza
    • PARP Inhibitor AZD2281
  • Procedure: Peripheral Blood Stem Cell Transplantation
    Undergo peripheral blood stem cell transplant
    Other Names:
    • PBPC transplantation
    • PBSCT
    • Peripheral Blood Progenitor Cell Transplantation
    • Peripheral Stem Cell Support
    • Peripheral Stem Cell Transplant
    • Peripheral Stem Cell Transplantation
  • Other: Pharmacokinetic Study
    Correlative studies
    Other Names:
    • PHARMACOKINETIC
    • PK Study
  • Biological: Rituximab
    Given IV
    Other Names:
    • ABP 798
    • BI 695500
    • C2B8 Monoclonal Antibody
    • Chimeric Anti-CD20 Antibody
    • CT-P10
    • IDEC-102
    • IDEC-C2B8
    • IDEC-C2B8 Monoclonal Antibody
    • MabThera
    • Monoclonal Antibody IDEC-C2B8
    • PF-05280586
    • Rituxan
    • Rituximab ABBS
    • Rituximab Biosimilar ABP 798
    • Rituximab Biosimilar BI 695500
    • Rituximab Biosimilar CT-P10
    • Rituximab Biosimilar GB241
    • Rituximab Biosimilar IBI301
    • Rituximab Biosimilar JHL1101
    • Rituximab Biosimilar PF-05280586
    • Rituximab Biosimilar RTXM83
    • Rituximab Biosimilar SAIT101
    • rituximab biosimilar TQB2303
    • rituximab-abbs
    • RTXM83
    • Truxima
  • Drug: Vorinostat
    Given PO
    Other Names:
    • L-001079038
    • MSK-390
    • SAHA
    • Suberanilohydroxamic Acid
    • Suberoylanilide Hydroxamic Acid
    • Zolinza
Study Arms  ICMJE Experimental: Treatment (olaparib, high-dose chemotherapy, transplant)
Patients receive olaparib PO BID on days -11 to -3, vorinostat PO on days -10 to -3, gemcitabine IV over 4.5 hours on days -9 and -4, busulfan IV over 3 hours on day -9 to -6, melphalan IV over 30 minutes on days -4 and -3, and undergo peripheral blood stem cell transplant IV over 30-60 minutes on day 0. Patients with CD20+ tumors also receive rituximab IV over 3-6 hours on day -10.
Interventions:
  • Drug: Busulfan
  • Drug: Gemcitabine
  • Drug: Melphalan
  • Drug: Olaparib
  • Procedure: Peripheral Blood Stem Cell Transplantation
  • Other: Pharmacokinetic Study
  • Biological: Rituximab
  • Drug: Vorinostat
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 8, 2018)
30
Original Estimated Enrollment  ICMJE
 (submitted: August 22, 2017)
60
Estimated Study Completion Date  ICMJE July 1, 2023
Estimated Primary Completion Date July 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with: A) diffuse large B-cell lymphoma (DLBCL) with one of the following: A.1) primary refractory (no CR to 1st line), A.2) high-risk relapse (CR1 < 6 months (mo), secondary International Prognostic Index [IPI] >1, high lactate dehydrogenase [LDH]), A.3) refractory relapse: no response to >= 1 salvage line and not eligible to receive other novel salvage therapies, such as chimeric antigen receptor T-cells (CAR-T) in a timely fashion or have already failed these; B) Hodgkin's with one of the following: B.1) primary refractory (no CR or progressive disease [PD] within 3 months), B.2) high-risk relapse (CR1 < 1 year, extranodal relapse, B symptoms), B.3) refractory relapse: no response to >= 1 salvage line C) T-non Hodgkin's lymphoma (T-NHL) with one of the following: C.1) primary refractory (no CR to 1st line), C.2) high-risk relapse (within 6 months), C.3) refractory relapse to >= 1 line of salvage. D) any other lymphoma that is refractory or relapsed and that does not qualify for autologous transplant protocols of higher priority.
  • Creatinine clearance estimated using the Cockcroft-Gault equation of >= 51 mL/min.
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be =< 5 x ULN.
  • Total bilirubin =< 2 x ULN or =< 3 x ULN if Gilbert's disease).
  • Forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLCOc) >= 50% of predicted).
  • Left ventricular ejection fraction (LVEF) >= 40%, no uncontrolled arrhythmias or symptomatic cardiac disease.
  • Eastern Cooperative Oncology Group (ECOG) performance status < 2.
  • Provision of informed consent prior to any study specific procedures.
  • Patients must have a life expectancy >= 16 weeks.
  • Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days and within 72 hours of study treatment and confirmed prior to receiving treatment on this study. Patients with positive results will be removed from the study. Postmenopausal is defined as: 1. amenorrheic for 1 year or more following cessation of exogenous hormonal treatments. 2. luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the postmenopausal range for women under 50. 3. radiation-induced oophorectomy with last menses > 1 year ago. 4. chemotherapy-induced menopause with > 1 year interval since last menses. 5. surgical sterilization (bilateral oophorectomy or hysterectomy). 6. female patients must agree to use a highly effective birth control method while on study and for at least 1 month after your last dose of study drug(s).
  • Male patients and their partners, who are sexually active and of childbearing potential, must agree to the use of two highly effective forms of contraception in combination, throughout the period of taking study treatment and for 3 months after last dose of study drug(s) to prevent pregnancy in a partner.
  • Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.
  • Prior apheresis of >= 3 million CD34+ cells/Kg.
  • Eligibility for ASCT is determined by the above inclusion criteria.

Exclusion Criteria:

  • Persistent toxicities (> Common Terminology Criteria for Adverse Events [CTCAE] grade 2) caused by previous cancer therapy, excluding alopecia.
  • Prior whole brain irradiation.
  • Active hepatitis B, either active carrier (hepatitis B surface antigen [HBsAg] +) or viremic (hepatitis B virus [HBV] deoxyribonucleic acid [DNA] >/= 10,000 copies/mL, or >= 2,000 IU/mL).
  • Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic hepatitis C or positive hepatitis C serology.
  • Active infection requiring parenteral antibiotics.
  • Patients who are known to be serologically positive for human immunodeficiency virus (HIV).
  • Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment.
  • Pregnancy.
  • Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1 endometrial carcinoma, or other solid tumors.
  • Resting electrocardiography (ECG) with correct QT interval (QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
  • Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
  • Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
  • Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML).
  • Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
  • Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
  • Uncontrolled non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
  • Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
  • Breast feeding women.
  • Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Yago Nieto, MD, PHD 713-792-8750 ynieto@mdanderson.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03259503
Other Study ID Numbers  ICMJE 2017-0073
NCI-2018-01094 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2017-0073 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Yago L Nieto M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP