Targeting Resistant Prostate Cancer With ATR and PARP Inhibition (TRAP Trial)

Status:Not yet recruiting
Conditions:Prostate Cancer, Cancer
Therapuetic Areas:Oncology
Age Range:18 - Any
Start Date:April 2019
End Date:July 2025
Contact:Zachary Reichert, M.D.

Use our guide to learn which trials are right for you!

A Multi-Center Phase II Study Testing the Activity of Olaparib and AZD6738 (ATR Inhibitor) in Metastatic Castration-Resistant Prostate Cancer

The purpose of this study is to test the effectiveness (how well the drugs work), safety, and
tolerability of the investigational drug combination of olaparib and AZD6738 for all patients
with metastatic castration-resistant prostate cancer.

Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures

2. Male ages 18 years and older at time of signing the informed consent form

3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 within 42 days
prior to registration

4. Histologic or cytologic proof of prostate adenocarcinoma (excluding small-cell or
neuroendocrine pathologies)

5. Metastatic prostate cancer on CT, MRI or Bone scan

6. Must have disease progression (while testosterone level is under 50 ng/dl) on prior
therapy prior to study entry defined as one (or more) of the following:

1. PSA progression defined as continuously rising PSA values measured a minimum of 1
week apart with a minimal starting value of 1.0 ng/mL

2. Progression of bidimensionally measurable soft tissue or nodal metastasis by CT
or MRI based on RECIST, v1.1

3. Progression of bone disease on bone scan as defined by two new lesions per PCWG3

7. Prior treatment with at least one of the following:

1. One line of therapy in mCRPC

2. Second generation anti-androgen (e.g. abiraterone, enzalutamide or apalutamide)
within the hormone-sensitive phase of disease AND progression occurs while on

8. Patients must be withdrawn from prior therapy for ≥3 weeks without PSA decline
(patients may remain on prior prednisone up to 10 mg total daily exposure at
provider's discretion).

9. Agree to undergo a biopsy of at least one metastatic site (if feasible) to determine
DNA repair status, unless prior metastatic tissue underwent next-generation sequencing
in a CLIA certified lab. If no site is reachable, or first biopsy
insufficient/unsuccessful, circulating analysis by Guardant360 panel will be done.

10. Treated with continuous androgen deprivation therapy (either surgical castration or
LHRH agonist/antagonist) with documented castrate level of serum testosterone (<50

11. At least 2 weeks since prior palliative radiation or 4 weeks for radiation to >30% of
the bone marrow or with a wide field of radiation

12. Patient must have normal organ and bone marrow function measured within 42 days prior
to registration as defined below

1. Hemoglobin ≥10 g/dL (with no blood transfusion or erythropoietin use within the
past 42 days)

2. Absolute neutrophil count ≥1.5x109/L

3. Platelet count ≥100x109/L (with no platelet transfusions within last 42 days)

4. Total bilirubin <1.5x ULN (unless the patient has documented Gilbert's disease
and <2.0x ULN should be used)

5. AST or ALT ≤ 2.5x ULN, unless liver metastases are present in which case they
cannot be ≥5x ULN

6. Glomerular filtration rate (GFR) ≥51 mL/min, as assessed using the Cockcroft-
Gault equation

13. Estimated life expectancy ≥12 weeks

14. Subjects must be surgically sterile or using an acceptable method of contraception
(defined as barrier methods in conjunction with spermicides) for the duration of the
study (from the time they sign consent) and for 6 months after the last dose of either
drug to prevent pregnancy in a partner. Female partners of male patients should also
use a highly effective form of contraception (as described in Appendix C) if they are
of childbearing potential. Male patients should not donate sperm throughout the period
of taking olaparib and for 6 months following the last dose of olaparib.

15. Patient is willing and able to comply with the protocol for the duration of the study,
including undergoing biopsy (if warranted), treatment, scheduled visits and

Exclusion Criteria:

1. A diagnosis of ataxia telangiectasia

2. Prior treatment with a PARP inhibitor (e.g. olaparib, veliparib, niraparib,
rucaparib), AZD6738 or other DNA-damage response agents

3. Cytotoxic chemotherapy, first- or second-generation antiandrogen or CYP17 inhibitors
are not permitted within 21 days or 5 half-lives of registration (whichever is

4. Major surgery < 2 weeks prior to enrolment; patients must have recovered from any
effects of major surgery

5. Persistent toxicities (≥CTCAE Grade 2) caused by previous cancer therapy, besides
Grade 2 alopecia and Grade 2 neuropathy (these are allowed).

6. Patients with current or prior MDS/AML or with features suggestive of MDS/AML

7. Any other malignancy which has been active or treated within the past 3 years, with
the exception of non-melanomatous skin cancer, or Ta bladder cancer

8. Patients with active brain metastases are excluded because of unknown penetration into
the CNS. A confirmatory scan for asymptomatic patients is not required. Patients with
a history of treated central nervous system (CNS) metastases are eligible provided
they meet all of the following criteria: disease outside the CNS is present, no
clinical evidence of progression since completion of CNS-directed therapy, minimum 3
weeks between completion of radiotherapy and registration and recovery from
significant (Grade ≥ 3) acute toxicity with no ongoing requirement for >10 mg of
prednisone per day or an equivalent dose of other corticosteroid. Patients with spinal
cord compression unless considered to have received definitive treatment for this and
evidence of clinically stable disease for 28 days.

9. Any of the following cardiac disease currently or within the last 6 months:

1. Unstable angina pectoris

2. Congestive heart failure (by New York Heart Association ≥ Class 2) or known
reduced LVEF < 55%

3. Acute myocardial infarction

4. Conduction abnormality not controlled with pacemaker or medication (e.g. complete
left bundle branch block or third-degree heart block)

5. Significant ventricular or supraventricular arrhythmias (patients with chronic
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities
are eligible).

6. Uncontrolled hypertension (Grade 2 or above) requiring clinical intervention

7. Patients at risk of brain perfusion problems, e.g. TIAs or history of pre-
syncope or syncopal episodes unexplained by reversible causes

10. Mean resting corrected QT interval> 470 msec for females and >450 for men, obtained
from 3 ECGs 2-5 minutes apart using the Fredericia formula. Absence of any factors
that increase the risk of QTc prolongation or risk of arrhythmic such as congenital
long QT syndrome, immediate family history of long QT syndrome or unexplained sudden
death under 40 year of age. Patients with relative hypotension (<90/60 mmHg) or
previously known clinically relevant orthostatic hypotension defined as a postural
hypotension ≥20 mmHg

11. Concomitant use of known potent cytochrome P (CYP) 3A inhibitors or inducers. The
required washout period prior to starting study treatment is five half-lives except
for St-Johns' wort, which is 3 weeks. See Appendix B.

- Patient has had prescription or non-prescription drugs or other products known to
be CYP3A4 and/or CYP2B6 substrates or CYP3A4 and/or CYP2B6 substrates with a
narrow therapeutic index. Exposure of other drugs metabolised by CYP3A4 and/or
CYP2B6 may be reduced and additional monitoring may be required. See Appendix B.

- The use of herbal supplements or 'folk remedies' (and medications and foods that
significantly modulate CYP3A activity) should be discouraged. If deemed
necessary, such products may be administered with caution and the reason for use
documented in the CRF. Please see Appendix B for further details.

12. As judged by the Investigator, any evidence of severe or uncontrolled systemic
diseases that places the patient at unacceptable risk of toxicity or non-compliance.
Examples include, but are not limited to, active bleeding diatheses, renal transplant,
uncontrolled major seizure disorder, severe COPD, superior vena cava syndrome,
extensive bilateral lung disease on High Resolution CT scan, severe Parkinson's
disease, active inflammatory bowel disease, psychiatric condition, immunocompromised
patients or active infection including any patient known to have hepatitis B,
hepatitis C and human immunodeficiency virus (HIV) or requiring systemic antibiotics,
antifungals or antiviral drugs. Screening for chronic conditions is not required

13. A known hypersensitivity to olaparib, AZD6738 or any excipient of the product or any
contraindication to the combination anti-cancer agent as per local prescribing

14. Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with the absorption of the study
medication, refractory nausea and vomiting, chronic gastrointestinal diseases or
previous significant bowel resection, with clinically significant sequelae that would
preclude adequate absorption of AZD6738

15. Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT).

16. Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable, for timing refer to inclusion
criteria no.12)

17. Involvement in the planning and/or conduct of the study

18. 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

19. Previous enrolment in the present study.

20. Has received a live vaccination with 2 weeks of enrollment.
We found this trial at
Ann Arbor, Michigan 48109
Principal Investigator: Zachary Reichert, M.D.
Ann Arbor, MI
Click here to add this to my saved trials