This is a first-time-in-man (FTIM) multicenter, dose escalation study designed to investigate
the safety, pharmacokinetics, and pharmacodynamics of AZD5153 in patients with malignant
solid tumors, including lymphomas.
The trial will be conducted in two parts, dose escalation and dose expansion. AZD5153 will be
investigated as a monotherapy and in combination with olaparib.
AZD5153 monotherapy (dose escalation):
This part of the study will enroll patients with advanced solid malignancies, including
lymphoma, and test safety and tolerability of AZD5153 administered as a monotherapy. The dose
escalation will proceed by two-fold increments or through lower doses suggested by the CRM
until an MTD as defined by dose-limiting toxicity is reached.
Single daily (QD) and twice daily (BID) dosing schedules will be explored in the monotherapy
cohort. Additional dose levels or dosing schedules may be evaluated and recommended by study
Safety Review Committee (SRC) based on the emerging PK and safety data.
When the AZD5153 monotherapy MTD is established, an expansion cohort consisting of up to 12
additional evaluable patients may be enrolled to confirm the safety and tolerability of the
MTD. The dose expansion will be initiated and will enroll patients with histologically or
cytologically confirmed platinum resistant or platinum-refractory high grade serous ovarian
(HGSO) cancer.
Mandatory tumor biopsies at screening for ovarian cancer patients will be required for
patient enrollment in the MTD dose expansion cohort. Optional on-treatment biopsies will be
requested from consenting patients in the ovarian expansion cohort.
AZD5153 + olaparib combination:
Dose escalation of AZD5153 in combination with olaparib will also be investigated while the
AZD5153 monotherapy dose escalation is ongoing and prior to determination of a monotherapy
MTD.
The starting dose of AZD5153 in combination with olaparib will be a dose that has been shown
to be safe and tolerated in monotherapy and has been chosen because clinical exposure
achieved at this dose is equivalent to preclinical exposure causing tumour growth inhibition
in animal models. If the starting dose in combination with olaparib is safe and tolerated,
the dose of AZD5153 will be escalated, using the same method as for the monotherapy part of
the study, keeping the olaparib dose fixed at 300 mg BID. Intermittent schedules as well as
continuous BID or QD dosing of AZD5153 in combination with 300 mg BID olaparib might be
tested until a safe and tolerated combination dose and schedule is determined. However, the
total dose per cycle of AZD5153 used in combination with olaparib won't exceed the total dose
per cycle that has been shown to be safe and tolerated as a monotherapy, and won't be higher
than the dose declared to be the monotherapy MTD. If intermittent dosing is explored then the
CRM will consider cumulative dosing rather than daily dosing.
AZD5153 and olaparib will be administered in continuous cycles of 21 days. The combination
dose escalation part will run in parallel with the AZD5153 monotherapy part (dose escalation
and expansion) and will continue until a safe and tolerated combination dose of the two
agents is declared. Mandatory paired tumor biopsies at screening and on-treatment will be
required for patients enrolled into the combination dose escalation.
Once a dose and schedule of AZD5153 in combination with olaparib is established, up to 12
additional evaluable patients might be enrolled to confirm the safety and tolerability of the
dose and schedule of AZD5153 and olaparib in one or more of the indications where clinical
activity is observed. Patients with platinum-resistant or platinum-refractory HGSO cancer,
triple negative breast cancer, metastatic castration resistant prostate cancer, or pancreatic
ductal adenocarcinoma will be eligible for the expansion cohort.
Inclusion Criteria for all Patients:
1. Patient must be able to understand the nature of the study and provide a signed and
dated, written informed consent prior to any study specific procedures, sampling or
analyses.
2. Patients should have the ability and willingness to comply with the study and
follow-up procedures.
3. Patients must have a solid tumor that is refractory to or intolerant of existing
therapies known to provide clinical benefit for their clinical condition.
4. Age ≥ 18
5. Adequate organ function, determined by:
- Absolute neutrophil count (ANC) ≥ 1.5 X 10^9/L
- Platelets ≥ 100 X 10^9/L
- Hemoglobin ≥ 9 g/dL
- aPTT ≤1.5 x ULN
- Total bilirubin ≤ 1.5 mg/dL
- ALT and AST ≤ 2.5 x ULN if no liver involvement or ≤ 5 x ULN with liver
involvement
- Creatinine <1.5 times ULN concurrent with creatinine clearance >50 mL/min
(measured or calculated by Cockcroft and Gault equation); confirmation of
creatinine clearance is only required when creatinine is >1.5 times ULN
6. Normotensive or well controlled blood pressure (BP) (<140/90), with or without current
antihypertensive treatment. If there is a diagnosis or history of hypertension,
patient must have adequately controlled BP on a maximum of 2 antihypertensive
medications, as demonstrated by 2 BP measurements taken in the clinical setting by a
medical professional within 1 week prior to enrollment. It is strongly recommended
that patients who are on antihypertensive medications be followed by a cardiologist or
a primary care physician for management of BP while on the study. Patients on a
hypertensive medication must be willing and able to check and record twice daily BP
readings for a minimum of 3 weeks.
7. ECOG performance status of 0-1
8. Life expectancy ≥ 3 months
9. Ejection fraction (EF) > 50%
10. Patients must have the ability to swallow and retain oral medication
11. Toxicities from prior therapy greater than CTCAE Grade 1 have resolved with the
exception of alopecia. Patients with Grade ≤ 2 neuropathy are eligible.
12. Male patients with female partners of child-bearing potential must be willing to use
two forms of acceptable contraception, including one barrier method, during their
participation in this study and for 6 months after stopping study treatment with
olaparib and/or AZD5153. Female partners of child-bearing potential of male patients
must use at least one of the two forms of acceptable contraception.
- Male patients must agree to refrain from donating sperm during their
participation in the study and until 6 months after the last treatment with
olaparib and/or AZD5153.
- Male patients will be counselled about the effects of the drug on their fertility
and the utility of freezing their sperm samples prior to the start of the study
should they wish to father children while on AZD5153 or during the 6 months after
stopping AZD5153.
13. Female patients must use two highly effective contraceptive measures. All methods of
contraception (with the exception of total abstinence) should be used in combination
with the use of a condom by a male sexual partner for intercourse. Female patients
must not be breast-feeding and must have a negative pregnancy test prior to start of
dosing if of childbearing potential or must have evidence of non-childbearing
potential by fulfilling one of the following criteria at screening:
- Post-menopausal women defined as aged more than 50 years and amenorrhoeic for at
least 12 months following cessation of all exogenous hormonal treatment.
- Documentation of irreversible surgical sterilization by hysterectomy, bilateral
oophorectomy, or bilateral salpingectomy, but not tubal ligation.
Additional Inclusion Criteria Specific for Monotherapy Dose Escalation:
1. Patients with histological or cytological confirmation of a malignant solid tumor
(locally advanced or metastatic) or lymphoma (any histology) that is refractory to
standard therapy(ies) or for which no standard therapy(ies) exists.
- Patients with a malignant solid tumor must have at least 1 lesion that can be
accurately measured at baseline by computed tomography (CT) scan according to Response
Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria (Eisenhauer et al. 2009)
and is suitable for repeated measurement.
2. Patients with lymphoma must have documented analysis of bone marrow infiltration from
biopsy carried out < 3 months of enrollment, or be able to undergo a new bone marrow
biopsy if such procedure was performed > 3 months prior to enrollment.
- Patients with a lymphoma must have at least 1 lesion that can be accurately assessed
at baseline by CT or CT and positron emission tomography (PET) according to the Cheson
criteria (Cheson et al 2007 and is suitable for repeated assessment.
3. Patient must agree to the collection of formalin fixed paraffin-embedded (FFPE) blocks
or slides from archival diagnostic histology samples, or a fresh pre-treatment biopsy
will be accepted.
Additional Inclusion Criteria specific for MTD monotherapy expansion and olaparib
combination dose escalation:
1. Patients with the following histologies that have at least 1 lesion that can be
accurately assessed at baseline by CT scan according to RECIST v1.1 criteria
(Eisenhauer et al. 2009) and is suitable for repeated assessment:
1. Histologically or cytologically confirmed platinum-resistant OR
platinum-refractory HGSO, fallopian, or primary peritoneal cancer in the relapsed
setting. Platinum-resistant disease is defined by progression within 6 months
following the last administered platinum-based regimen. Platinum-refractory
disease is defined by lack of at least a partial response while on
platinum-containing regimens.
2. Triple-negative breast cancer (TNBC) that is refractory to standard therapy(ies)
or for which no standard therapy(ies) exists
3. Refractory metastatic castrate-resistant prostate cancer (mCPRC)
4. Pancreatic ductal adenocarcinoma (PDAC) with progression on standard treament
2. Patients will be allowed on study regardless of their BRCA mutational status.
Information about their BRCA mutational status or other HRD gene mutational status
must be collected if patients have been tested as part of their standard of care.
3. Previous response to olaparib or other PARPi is not required
4. Patients must have at least 1 site of disease amenable to biopsy at screening, and
must be a candidate for tumor biopsy. Patients must be willing to undergo a new tumor
biopsy during screening. An on-treatment tumor biopsy will be mandatory in the
olaparib combination dose escalation portion of this study, and optional from
consenting patients in the monotherapy expansion at MTD.
5. For the olaparib combination portion of this study, patients are required to have
hemoglobin ≥10 g/dL at study entry.
Exclusion Criteria:
1. Patients who have been treated with most recent chemotherapy, radiotherapy, hormonal
therapy, immunotherapy or investigational drugs within 21 days or 5 half-lives
(whichever is shorter) from enrollment.
2. Minimum wash-out period for previous PARPi therapy is at least 14 days or 5 half-lives
whichever is shorter, or until toxicity from previous PARPi therapy has fully
recovered.
3. Patient received more than 5 prior lines of treatment for an advanced solid tumor
(including HGSO cancer, TNBC, mCRPC, or PDAC). Patients with lymphoma will be able to
enroll without a restriction in the number of previous therapies received, if they
otherwise meet eligibility criteria.
4. Major surgery (excluding placement of vascular access) ≤ 21 days from the beginning of
enrollment or minor surgical procedures ≤ 7 days. No waiting is required following
implantable port and catheter placement.
5. Patient is unable to swallow oral medications or has a gastrointestinal disorder
(e.g., malabsorption) that would jeopardize intestinal absorption of AZD5153 and
olaparib.
6. Treatment with any of the following:
- Patient has had prescription or non-prescription drugs or other products known to
be strong or moderate inhibitors/inducers of CYP3A4/5, or CYP3A4/5 sensitive
substrates or substrates with a narrow therapeutic range, which cannot be
discontinued 2 weeks prior to the first day of dosing and withheld throughout the
study until 2 weeks after the last dose of AZD5153 and/or olaparib.
- Drugs that are sensitive substrates of the transporters P-gp, UGT1A1, BCRP,
OATP1B1, OAT3, OCT1, OCT2, MATE1 and MATE2K.
- Herbal preparations/medications are not allowed throughout the study. These
herbal medications include, but are not limited to: St. John's wort, kava,
ephedra (ma huang), ginkgo biloba, dehydroepiandrosterone, yohimbe, saw palmetto,
and ginseng. Patients should stop using these herbal medications 14 days prior to
the first dose of AZD5153 and/or olaparib.
- Drugs known to prolong QT interval or induce Torsades de Pointes.
7. Refractory nausea and vomiting, previous significant bowel resection that would
preclude adequate absorption of study drug and chronic gastrointestinal disease
including active or prior documented inflammatory bowel disease.
8. Patient has a history of tuberculosis.
9. Patients receiving a live attenuated vaccine ≤28 days before the first dose of study
drug.
10. Spinal cord compression or brain metastases unless asymptomatic, treated and stable
and not requiring steroids for at least 4 weeks prior to start of study treatment.
11. A diagnosis of MDS or secondary AML (for olaparib combination dose escalation only)
12. As judged by the Investigator, any evidence of severe or uncontrolled systemic
diseases, including uncontrolled hypertension, active bleeding diatheses, or active
infection including hepatitis B, hepatitis C, human immunodeficiency virus (HIV) or
other comorbidity that renders the patient unsuitable for participation in the study.
Screening for chronic conditions is not required.
13. Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTcF) >450 msec obtained from 3
electrocardiograms (ECGs).
- Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG e.g., complete left bundle branch block, third degree heart block.
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalemia, congenital long QT syndrome, family
history of long QT syndrome or unexplained sudden death under 40 years of age.
14. History of hypersensitivity to active or inactive excipients of AZD5153 and/or
olaparib or drugs with a similar chemical structure or class to AZD5153 and/or
olaparib.
15. Patients with non-Hodgkin lymphoma (NHL) at high risk for developing tumor lysis
syndrome are not eligible for the monotherapy dose escalation part of this study.
16. Judgment by the Investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and
requirements.
17. Psychological, familial, sociological, or geographical conditions that do not permit
compliance with the protocol.
