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.
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.
