Clinical Trials /

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

NCT03259503

Description:

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.

Related Conditions:
  • Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Olaparib and High-Dose Chemotherapy in Treating Patients With Relapsed or Refractory Lymphomas Undergoing Stem Cell Transplant
  • Official Title: Olaparib Combined With High-Dose Chemotherapy for Refractory Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: 2017-0073
  • SECONDARY ID: NCI-2018-01094
  • SECONDARY ID: 2017-0073
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03259503

Conditions

  • 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

Interventions

DrugSynonymsArms
Busulfan1, 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-19508Treatment (olaparib, high-dose chemotherapy, transplant)
GemcitabinedFdC, dFdCyd, DifluorodeoxycytidineTreatment (olaparib, high-dose chemotherapy, transplant)
MelphalanAlanine 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-19813Treatment (olaparib, high-dose chemotherapy, transplant)
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Treatment (olaparib, high-dose chemotherapy, transplant)
RituximabABP 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, TruximaTreatment (olaparib, high-dose chemotherapy, transplant)
VorinostatL-001079038, MSK-390, SAHA, Suberanilohydroxamic Acid, Suberoylanilide Hydroxamic Acid, ZolinzaTreatment (olaparib, high-dose chemotherapy, transplant)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (olaparib, high-dose chemotherapy, transplant)ExperimentalPatients 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.
  • Busulfan
  • Gemcitabine
  • Melphalan
  • Olaparib
  • Rituximab
  • Vorinostat

Eligibility Criteria

        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.
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicities (DLT)
Time Frame:Up to 30 days
Safety Issue:
Description:All adverse events will be tabulated by dose, and a Bayesian DLT curve will be fit.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:At 2 years
Safety Issue:
Description: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.
Measure:Event-free survival (EFS)
Time Frame:At 2 years
Safety Issue:
Description: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.
Measure:Objective response (OR)
Time Frame:Up to 100 days
Safety Issue:
Description:OR will be tabulated by dose, and a Bayesian DLT curve will be fit.
Measure:Complete response (CR)
Time Frame:At 100 days
Safety Issue:
Description:CR will be tabulated by dose, and a Bayesian DLT curve will be fit.
Measure:Incidence of adverse events
Time Frame:At 2 years
Safety Issue:
Description:All adverse events will be tabulated by dose, and a Bayesian DLT curve will be fit.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

November 15, 2019