Inclusion Criteria:
- Subjects must have histologically confirmed malignancy that is metastatic or
unresectable and for which standard curative measures do not exist or are no longer
effective
- Patients in dose expansion Cohort A (intrinsic resistance), must have:
- Prior treatment with PARP inhibitors
- Disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) at
1st re-staging, and
- Germline or somatic mutations in BRCA1 or BRCA2
- Patients in dose expansion Cohort B (acquired resistance) must have:
- Prior treatment with PARP inhibitors,
- Complete/partial response followed by disease progression per RECIST, and
- Germline or somatic mutations in any of the following deoxyribonucleic acid (DNA)
damage response (DDR) genes: BRCA1, BRCA2, BRIP1, FANCA, PALB2, or the non-DDR
gene marker cyclin E amplification. Local testing in Clinical Laboratory
Improvement Act (CLIA)-certified laboratory will be accepted. All alterations
will be reviewed by MD Anderson's Precision Oncology Decision Support (PODS)
team. No variants of uncertain significance (VUS) will be allowed as the
qualifying genetic mutation. Recruitment of patients with relevant molecular
aberrations in the dose escalation phase is encouraged but not mandated.
- Subjects must have RECIST measureable disease and a tumor that is safely accessible
for biopsy and must be willing to undergo biopsy
- Subjects must have received at least one line of systemic therapy in the
advanced/metastatic setting. Subjects with diseases without known effective options,
and subject who have declined standard or care therapy prior to study introduction are
also eligible
- Any prior palliative radiation therapy must have been completed at least 14 days prior
to the start of study drugs, and patients must have recovered from any acute adverse
effects prior to the start of study treatment
- Human immunodeficiency virus (HIV)-infected (HIV1/2 antibody-positive) patients may
participate if they meet all the following eligibility requirements:
- They must be on an anti-retroviral regimen with evidence of at least two
undetectable viral loads within the past 6 months on this same regimen; the most
recent undetectable viral load must be within the past 12 weeks
- They must have a CD4 count >= 250 cells/uL over the past 6 months on this same
anti-retroviral regimen and must not have had a CD4 count < 200 cells/ul over the
past 2 years, unless it was deemed related to the cancer and/or
chemotherapy-induced bone marrow suppression. For patients who have received
chemotherapy in the past 6 months, a CD4 count < 250 cells/ul during chemotherapy
is permitted as long as viral loads were undetectable during this same
chemotherapy
- They must have an undetectable viral load and a CD4 count >= 250 cells/uL within
7 days of enrollment
- They must not be currently receiving prophylactic therapy for an opportunistic
infection and must not have had an opportunistic infection within the past 6
months. Monitoring for HIV-infected patients should include:
- Viral load and CD4 count every 12 weeks (q12w)
- If CD4 count drops to less than 200 cells/ul while on study, initiate viral
load test. If viral load proves undetectable at this time, continue CD4 and
viral load checks every 8 weeks (q8w). If 2 consecutive viral load tests are
undetectable, revert to q12w testing for CD4 and viral load testing
- If an opportunistic infection occurs with a CD4 count of < 200 cells/ul,
hold study treatment. Initiate treatment of the infection and continue to
hold study treatment; once clinically stable, CD4 count is > 200 cells/ul
and viral load has remained undetectable, reinitiate study treatment
- Patients with a past or resolved hepatitis B virus (HBV) infection (defined as the
presence of hepatitis B core antibody and absence of HBsAg) are eligible. Active HBV
is defined by a known positive HBV surface antigen (HBsAg) result. Patients positive
for hepatitis C virus (HBC) antibody are eligible only if polymerase chain reaction
(PCR) is negative for HCV RNA. Patients with known active HBV or HBC infection are
ineligible
- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression within
28 days
- Patients with new or progressive brain metastases (active brain metastases) or
leptomeningeal disease are eligible if the treating physician determines that
immediate CNS specific treatment is not required and is unlikely to be required during
the first cycle of therapy
- Absolute neutrophil count (ANC) >= 1500/uL (within 7 days of study drugs initiation)
- Hemoglobin (Hgb) >= 10 g/dL (within 7 days of study drugs initiation) with no blood
transfusion in the past 28 days
- Platelets >= 100,000/uL (within 7 days of study drugs initiation)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
=< 2.5 X upper limit of normal (ULN) (within 7 days of study drugs initiation), unless
liver metastases are present in which case they must be =< 5 X ULN
- Serum bilirubin within normal limits (WNL) (within 7 days of study drugs initiation)
or =< 1.5 X ULN in patients with liver metastases, or total bilirubin =< 3 X ULN with
direct bilirubin WNL in patients with well-documented Gilbert's syndrome
- Serum creatinine =< 1.5 X ULN (within 7 days of study drugs initiation). If elevated,
check creatinine clearance (CrCl) with cut off >= 51 mL/min as calculated by the
Cockcroft-Gault method or based on a 24-hour urine test (confirmation of creatinine
clearance is only required when serum creatinine is > 1.5 X institutional ULN)
- The effects of AZD1775 and olaparib on the developing human fetus are either unclear
or are known to be teratogenic, women of childbearing potential and their partners,
who are sexually active, must agree to the use of TWO highly effective forms of
contraception in combination. This should be started from the signing of the informed
consent and continue throughout the period of taking study treatment and for at least
1 month after last dose of study drug(s), or they must totally/truly abstain from any
form of sexual intercourse. Male patients must use a condom during treatment and for 3
months after the last dose of study drug when having sexual intercourse with a
pregnant woman or with a woman of childbearing potential. Female partners of male
patients should also use a highly effective form of contraception if they are of
childbearing potential. Male patients should not donate sperm throughout the period of
taking study drugs and for 3 months following the last dose of study drugs.
- Acceptable non-hormonal birth control methods include:
- Total/True abstinence: When the patient refrains from any form of sexual
intercourse and this is in line with their usual and/or preferred lifestyle;
this must continue for the total duration of the trial and for at least 1
month after the last dose of study drug for women of child bearing
potential. For male patients, 3 months after last dose. (Periodic abstinence
[e.g., calendar, ovulation, symptothermal, post-ovulation methods, or
declaration of abstinence solely for the duration of a trial] and withdrawal
are not acceptable methods of contraception.)
- Vasectomized sexual partner PLUS male condom. With participant assurance
that partner received post-vasectomy confirmation of azoospermia
- Tubal occlusion PLUS male condom
- Intrauterine device (IUD) PLUS male condom. Provided coils are copper-banded
- Acceptable hormonal methods:
- Normal and low dose combined oral pills PLUS male condom
- Cerazette (desogestrel) PLUS male condom. Cerazette is currently the only
highly efficacious progesterone based pill
- Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom
- Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom
- Norelgestromin / ethinyl estradiol (EE) transdermal system PLUS male condom
- Intrauterine system (IUS) device (e.g., levonorgestrel releasing IUD-Mirena)
PLUS male condom
- Intravaginal device (e.g., EE and etonogestrel) PLUS male condom
- In the case of use of oral contraception, women should be stable on the same
pill before taking study treatment
- Note: oral contraceptives are allowed but should be used in conjunction with
a barrier method of contraception due to unknown effect of drug-drug
interaction. Women are considered post-menopausal and not of childbearing
potential if they have had 12 or more months of natural (spontaneous)
amenorrhea following cessation of exogenous hormonal treatment with an
appropriate clinical profile (e.g. age appropriate, history of vasomotor
symptoms) or have had surgical bilateral oophorectomy (with or without
hysterectomy). In the case of oophorectomy alone, she will be considered not
of childbearing potential only when her reproductive status has been
confirmed by follow up hormone level assessment
- Male patients will be advised to arrange for the freezing of sperm samples prior to
the start of the study should they wish to father children while on study drugs or
during the 3 months after stopping study drugs
- Male or female patient >= 18 years of age. Because no dosing or adverse event data are
currently available on the use of AZD1775 in combination with olaparib in patients <
18 years of age, children are excluded from this study, but will be eligible for
future pediatric trials
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1
(Karnofsky >= 70%)
- Ability to understand and the willingness to sign a written informed consent document.
Participants with impaired decision-making capacity (IDMC) who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible. Has read and understands the informed consent form (ICF) and has given
written informed consent (IC) prior to any study procedures
- Willingness and ability to comply with study and follow-up procedures
Exclusion Criteria:
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to AZD1775 or olaparib
- Use of anti-cancer treatment drug =< 28 days or 5 half-lives (whichever is shorter)
prior to the first dose of study treatment. For drugs for which 5 half-lives is =< 21
days, a minimum of 10 days between termination of the prior treatment and
administration of study treatment is required
- Use of radiotherapy (except for palliative reasons) within =< 28 days prior to study
treatment
- No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal anticancer therapy
radiotherapy), biological therapy or other novel agent is to be permitted while the
patient is receiving study medication. Patients with castration-resistant prostate
cancer on luteinizing hormone-releasing hormone (LHRH) analogue treatment for more
than 6 months are allowed entry into the study and may continue at the discretion of
the investigator
- Concomitant use of CYP3A inducers/inhibitors:
- Concomitant use of known strong CYP3A inhibitors (e.g., 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 (e.g., 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 study treatment is 5 weeks for enzalutamide or
phenobarbital and 3 weeks for other agents
- Major surgical procedures =< 28 days of beginning study treatment, or minor surgical
procedures =< 7 days. Patients must have recovered from any of the effects of any
major surgery. No waiting period required following port-a-cath placement or other
central venous access placement
- Known malignant central nervous system (CNS) disease other than neurologically stable,
treated brain metastases - defined as metastasis having no evidence of progression or
hemorrhage for at least 2 weeks after treatment (including brain radiotherapy). Must
be off any systemic corticosteroids for the treatment of brain metastases for at least
14 days prior to enrollment. Subjects with brain metastases must have completed
treatment, either surgery or radiation, and be stable for at least 28 days off steroid
prior to screening. A brain magnetic resonance imaging (MRI) demonstrating there is no
current evidence or progressive brain metastases is required in subjects with previous
brain metastasis. Patients with breast tissue expanders may have brain computed
tomography (CT) for assessment
- Patients with either previous or current myelodysplastic syndrome (MDS)/acute myeloid
leukemia (AML) or features suggestive of MDS/AML (e.g., persistent anemia or other
blood dyscrasias) are excluded because olaparib and AZD1775 are agents with the
potential to induce MDS/AML
- AZD1775 should not be given to patients who have a history of Torsades de pointes
(TdP) unless all risk factors that contributed to TdP have been corrected
- Any of the following cardiac diseases currently or within the last 6 months:
- Unstable angina pectoris
- Acute myocardial infarction
- Congestive heart failure >= class 2 (as defined by New York Heart Association
[NYHA])
- Conduction abnormality not controlled with pacemaker or medication
- Significant ventricular or supraventricular arrhythmias (patients with chronic
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities
are eligible)
- Participants with a mean resting corrected QT interval (QTc) >= 480 msec at study
entry, as calculated by the Frederica formula (QTcF) by institutional standards
obtained from an electrocardiogram (ECG) or congenital long QT syndrome. (Note: if one
ECG demonstrates a QTcF > 480 msec, then a mean QTcF of =< 480 msec obtained from 3
ECGs 2-5 minutes apart is required at study entry
- Patients considered a poor medical risk due to a serious, uncontrolled medical
disorder, 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 with uncontrolled intercurre
