Phase I Study of AZD5363 + Olaparib + Durvalumab in Patients With Advanced or Metastatic Solid Tumor Malignancies
Phase I Study of AZD5363 + Olaparib + Durvalumab in Patients With Advanced or Metastatic Solid Tumor Malignancies
This is a Phase 1 dose-escalation study to evaluate the safety and tolerability of
 combination treatment of AZD5363 + Olaparib + Durvalumab and to determine the RP2D in
 patients with advanced or metastatic solid tumor malignancies.

 The purpose of this trial is to determine if combination treatment of drugs, Olaparib,
 AZD5363 and Durvalumab has beneficial effects in advanced or metastatic cancers and to
 determine the effects it has on patients and their cancer.

 Primary Objectives

 • To evaluate the safety and tolerability of combination treatment AZD5363 + Olaparib +
 Durvalumab and determine the Maximum Tolerated Dose (MTD), Dose-Limiting Toxicities (DLTs),
 and Recommended Phase 2 Dose (RP2D) for patients with advanced or metastatic solid tumor
 malignancies.

 Secondary Objectives

 -  To determine the pharmacodynamics (PDn) of combination treatment AZD5363 + Olaparib +
 Durvalumab in patients with advanced or metastatic solid tumor malignancies

 -  To describe anti-tumor response using immune RECIST of combination treatment AZD5363 +
 Olaparib + Durvalumab in patients with advanced or metastatic solid tumor malignancies

 Exploratory Objectives

 -  To evaluate anti-tumour response using RECIST v1.1 for combination treatment AZD5363 +
 Olaparib + Durvalumab in patients with advanced or metastatic solid tumor malignancies

 -  To explore molecular correlates of the relationship between mutations in Akt/
 PIK3CA/PTEN pathway and response to AZD5363 +Olaparib+ Durvalumab

 -  To understand the role of tumour microenvironment in regulation of intratumoral immune
 regulators (i.e. T-regulatory cells) in improving response to Durvalumab

 -  To understand the role of AZD5363 as an immunomodulator

 -  To evaluate the role of PD-1 and PDL-1 immunohistochemical and tumour MMR status in
 predicting response to immune check point inhibitors.
This study is divided into 3 different periods: Screening, Treatment, and End of Treatment
 Before taking the treatment, patients will have some tests and procedures done to make sure
 they are eligible for the study (Screening). Then they will enter the Treatment period, where
 Durvalumab, Olaparib and AZD5363 will be administered to them. If they stop taking your study
 medication for any reason, an End of Treatment visit will be conducted within 30 days after
 the last doze of study medication.

 Screening Assessment:

 -  Written Informed Consent

 -  Inclusion/Exclusion Criteria

 -  Complete Medical History

 -  Prior therapies and PFS on last anti-cancer therapy

 -  Complete Physical Examination amp; ECOG

 -  Standard Clinical Neurologic Examination

 -  BSA

 -  Weight

 -  Blood Pressure, Pulse and Temperature

 -  Oxygen Saturation (Pulse Oximetry)

 -  12-lead Electrocardiogram

 -  HbA1c and fasting glucose

 -  Serum Chemistry (renal panel 2) amp; Serum Troponin Level

 -  Amylase and lipase

 -  Liver function test

 -  Serum Pregnancy Test (for women of childbearing potential)

 -  Thyroid function test including TSH and free T4

 -  Coagulation Parameters

 -  Chest X-ray (if clinically indicated)

 -  CBC with Differential

 -  CT or MRI Scan Tumor Measurement

 -  PET-CT/PET-MRI Scan Tumor Measurement (optional)

 -  Transthoracic Echo/ MUGA

 -  Baseline Symptoms

 -  Concomitant Medication Assessments

 -  Tumor Biopsy

 -  Fasting lipids

 -  Assessment for hepatitis B surface antigen, hepatitis C antibodies and HIV antibodies

 -  Urinalysis

 Run-in Period (Day -14 until Day 0)

 -  Complete or Symptom Directed Physical Examination amp; ECOG

 -  Standard Clinical Neurologic Examination

 -  BSA

 -  Weight

 -  Blood Pressure, Pulse and Temperature

 -  12-lead Electrocardiogram

 -  Serum Chemistry (renal panel 2)

 -  Serum Troponin Level

 -  Coagulation Parameters

 -  Liver panel including amylase and lipase

 -  CBC with Differential

 -  Oxygen Saturation (Pulse Oximetry)

 -  Drug Administration only for AZD5363

 -  Pharmacodynamics (PDn) blood

 -  AE Assessments

 -  Concomitant Medication Assessments

 Cycle 1 (every week)

 -  Complete or Symptom Directed Physical Examination amp; ECOG

 -  Standard Clinical Neurologic Examination

 -  BSA

 -  Weight

 -  Blood Pressure, Pulse and Temperature

 -  HbA1c ( To be performed on cycle 1 day 1and every 12 week thereafter)

 -  12-lead Electrocardiogram

 -  Serum Chemistry (renal panel 2)

 -  Serum Troponin Level

 -  Coagulation Parameters

 -  Liver panel including amylase and lipase

 -  CBC with Differential

 -  Thyroid Stimulating Hormone (TSH), ACTH (only every 4 weeks, D1 of every cycle)

 -  Oxygen Saturation (Pulse Oximetry)

 -  Drug Administration

 -  Pharmacodynamics (PDn)

 -  AE Assessments

 -  Concomitant Medication Assessments

 -  Urinalysis

 Cycle 2 and Cycle 3 (every 2 weeks)

 -  Complete or Symptom Directed Physical Examination amp; ECOG

 -  Standard Clinical Neurologic Examination

 -  BSA

 -  Weight

 -  Blood Pressure, Pulse and Temperature

 -  12-lead Electrocardiogram

 -  Serum Chemistry (renal panel 2)

 -  Liver panel including amylase and lipase

 -  Serum Troponin Level

 -  Coagulation Parameters

 -  CBC with Differential

 -  Oxygen Saturation (Pulse Oximetry)

 -  Drug Administration

 -  Pharmacodynamics (PDn) blood (Cycle 2 Day 1)

 -  AE Assessments

 -  *CT or MRI Scan Tumor Measurement (end of Cycle 2every 8 weeks in the last week of the
 cycle)

 -  Concomitant Medication Assessments

 -  Fasting lipids

 -  Urinalysis

 -  Transthoracic Echo/ MUGA (only if indicated)

 Cycle 4 and Beyond (every 4 weeks)

 -  Complete or Symptom Directed Physical Examination amp; ECOG

 -  Weight

 -  Blood Pressure, Pulse and Temperature

 -  Standard Clinical Neurologic Examination

 -  Oxygen Saturation (Pulse Oximetry)

 -  12-lead Electrocardiogram

 -  Transthoracic Echo/ MUGA (only at C4D1)

 -  Fasting lipids

 -  Serum Chemistry (renal panel 2)

 -  Serum Troponin Level

 -  Thyroid Stimulating Hormone (TSH), ACTH

 -  Coagulation Parameters

 -  CBC with Differential

 -  *CT or MRI Scan Tumor Measurement (end of Cycle 4 and every 8 weeks thereafter)

 -  Drug Administration

 -  *PET-CT/PET-MRI Scan Tumor Measurement (optional) (every 8 weeks)

 -  AE Assessments

 -  Concomitant Medication Assessments

 -  Transthoracic Echo/ MUGA (only if indicated)

 Final Visit

 -  Complete Physical Examination amp; ECOG

 -  Weight

 -  Blood Pressure, Pulse and Temperature

 -  Standard Clinical Neurologic Examination

 -  Oxygen Saturation (Pulse Oximetry)

 -  12-lead Electrocardiogram and troponin level

 -  Transthoracic Echo/ MUGA

 -  Fasting lipids

 -  Serum Chemistry

 -  Coagulation Parameters

 -  CBC with Differential

 -  Thyroid Stimulating Hormone (TSH)

 -  AE assessments

 -  Concomitant Medication Assessment
Inclusion Criteria:

 1. All patients must sign an informed consent in accordance with local institutional
 guidelines.

 2. Age >= 21

 3. Histologically confirmed advanced or metastatic solid tumors who have radiological
 evidence of progressive disease on study entry and at least 2 measurable lesions, that
 is deemed unlikely to benefit from further conventional therapy, or for which no
 standard therapy is available. Although optional, where practicable and safe, all
 effort should be made by the investigator to obtain serial tumour biopsies from
 patients enrolled.

 4. Provision of an archived tumour tissue block (or at least 10 newly cut unstained
 slides) where such samples exist in a quantity sufficient to allow for analysis

 5. Any number of prior chemotherapy regimens will be allowed and may include biologics

 6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1;

 7. Patients must have adequate bone marrow function and organ function within 2 weeks of
 study treatment;

 -  Adequate hematologic function defined as:

 (i) platelets >= 100 x 109/L in dose escalation phase, (ii) hemoglobin >= 6.21
 mmol/L or 10 g/dL, (iii) ANC >= 1.5 x 109/L, (iv) WBC >= 3.0 x 109/L. Up to 5%
 deviation is tolerated. Transfusions and growth factors are allowed prior to and
 throughout the study.

 -  Hepatic function: bilirubin < 1.5 times the upper limit of normal (ULN), ALT and
 AST < 2.5 times ULN. For patients with hepatic metastasis ALT and AST < 5 times
 ULN is permitted. Up to 10% deviation is acceptable.

 -  Adequate renal function: estimated creatinine clearance of >= 60 mL/min,
 calculated using the formula of Cockcroft and Gault: (140-Age) • Mass (kg)/(72 •
 creatinine mg/dL); multiply by 0.85 if female.

 -  Amylase and lipase <= 1.5 x ULN;

 -  Alkaline phosphatase limit <= 2.5 x ULN (<= 5 x ULN for patients with liver
 involvement of their cancer);

 -  International normalization ratio (INR) (if not on anticoagulation therapy) and
 partial thromboplastin time (PTT) <= 1.5 x ULN;

 -  Normal TSH and ACTH

 8. Females of childbearing potential who are sexually active with a non sterilized male
 partner must use at least 2 highly effective method of contraception from the time of
 screening and must agree to continue using such precautions for 180 days after the
 last dose of durvalumab + any drug combination therapy or 90 days after the last dose
 of durvalumab monotherapy. Non-sterilized male partners of a female patient must use
 male condom plus spermicide throughout this period. Cessation of birth control after
 this point should be discussed with a responsible physician. Not engaging in sexual
 activity for the total duration of the drug treatment and the drug washout period is
 an acceptable practice; however, periodic abstinence, the rhythm method, and the
 withdrawal method are not acceptable methods of birth control. Female subjects should
 also refrain from breastfeeding throughout this period. Acceptable methods of
 contraception are as below:

 -  Established use of oral, injected or implanted hormonal methods of contraception.

 -  Placement of an intrauterine device or intrauterine system.

 -  Barrier methods of contraception: condom or occlusive cap (diaphragm or
 cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.

 -  Male partner sterilisation (with the appropriate post-vasectomy documentation of
 the absence of sperm in the ejaculate).

 -  True abstinence

 -  It is not known whether AZD5363 has the capacity to affect the metabolism of
 hormonal contraceptives, so hormonal contraception should also be combined with a
 barrier method of contraception or patients must have evidence of
 non-child-bearing potential by fulfilling one of the following criteria at
 screening:

 -  Post-menopausal: defined as aged more than 50 years and amenorrhoeic for at
 least 12 months following cessation of all exogenous hormonal treatments.

 -  Documentation of irreversible surgical sterilisation by hysterectomy,
 bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation

 9. Non-sterilized males who are sexually active with a female partner of childbearing
 potential must use a male condom plus spermicide from screening through 180 days after
 receipt of the final dose of durvalumab + any drug combination therapy or 90 days
 after receipt of the final dose of durvalumab monotherapy. Not engaging in sexual
 activity is an acceptable practice; however, occasional abstinence, the rhythm method,
 and the withdrawal method are not acceptable methods of contraception. Male patients
 are required to use barrier methods of contraception and refrain from sperm donation
 throughout the study and for 180 days after the last dose of study drug. Male patients
 wishing to father children should be advised to arrange for freezing of sperm samples
 prior to the start of study treatment. Breastfeeding women are also excluded from
 study entry.

 10. At time of registration, if the patient has had previous treatment it must have been
 at least 4 weeks since major surgery or radiation therapy; four weeks from any other
 previous anti-cancer therapy including biologics. Patients must have recovered from
 their treatment-related events to <=G1 with the exception of alopecia and neuropathy
 (<= G2 sufficient).

 11. Life expectancy greater than 12 weeks

 12. Patients must weigh at least 30kg

 13. Patients previously treated on check point inhibitor or PARP inhibitor monotherapy
 will be allowed on study

 Exclusion Criteria:

 1. Patients with significant medical illness that in the investigator's opinion cannot be
 adequately controlled with appropriate therapy or would compromise the patient's
 ability to tolerate this therapy;

 2. Radiation (except planned or ongoing palliative radiation to bone outside of the
 region of measurable disease) <= 3 weeks prior to starting first dose of study
 medication

 3. Participation in another clinical study with an investigational product (IP) within 30
 days of the first dose of AZD5363 or matching placebo.Treatment with any of the
 following:

 -  Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment

 -  Any investigational agents or study drugs from a previous clinical study within
 30 days of the first dose of study treatment (<= 4 weeks for previous PD-1/PD-L1)

 -  Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks of the
 first dose of study treatment, except hormonal therapy with LHRH analogues for
 medical castration in patients with prostate cancer, which are permitted

 -  Potent inhibitors or inducers or substrates of CYP3A4 or substrates of CYP2D6
 within 2 weeks before the first dose of study treatment (3 weeks for St John's
 Wort )

 4. Uncontrolled hypertension or controlled hypertension (<140/90) on more than 3
 antihypertensive agents

 5. Clinically significant abnormalities of glucose metabolism as defined by any of the
 following:

 o Diabetes mellitus type I

 o Fasting plasma glucose [fasting is defined as no calorific intake for at least 8
 hours]: (i) >= 7.0mmol/L (126 mg/dL) for those patients without a pre-existing
 diagnosis of Type 2 diabetes mellitus (ii) >= 9.3 mmol/L (167mg/dL) for those patients
 with a pre-existing diagnosis of Type 2 diabetes mellitus (iii) Glycosylated
 haemoglobin (HbA1C) >=8.0% (63.9 mmol/mol). (iv) Requirement for insulin or more than
 two oral hypoglycaemic medications for routine diabetic management and control

 6. Major surgical procedure within the last 28 days

 7. Active or prior documented autoimmune or inflammatory disorders (including
 inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the
 exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or
 Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
 arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
 criterion:

 -  Subjects with vitiligo or alopecia

 -  Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
 replacement

 -  Any chronic skin condition that does not require systemic therapy

 -  Subjects without active disease in the last 5 years may be included but only
 after consultation with the study physician

 -  Subjects with celiac disease controlled by diet alone

 8. Any of the following cardiac criteria:

 -  Mean resting corrected QT interval (QTc) >470 msec obtained from 3 consecutive
 ECGs.

 -  Any clinically important abnormalities in rhythm, conduction or morphology of
 resting ECG eg, 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, hypokalaemia, potential for torsades de pointes,
 congenital long QT syndrome, family history of long QT syndrome or unexplained
 sudden death under 40 years of age or any concomitant medication known to prolong
 the QT interval.

 -  Experience of any of the following procedures or conditions in the preceding 6
 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial
 infarction, angina pectoris, congestive heart failure NYHA Grade >=2.

 -  Uncontrolled hypotension - SBP <90 mmHg and/or DBP <50 mmHg.

 -  Cardiac ejection fraction outside institutional range of normal or <50%
 (whichever is higher) as measured by echocardiogram (or MUGA scan if an
 echocardiogram cannot be performed or is inconclusive).Left ventricular ejection
 fraction (LVEF) below lower limit of normal for site.

 9. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, known immunodeficiency syndrome,
 uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial
 lung disease (history of interstitial lung disease will also be excluded), serious
 chronic gastrointestinal conditions associated with diarrhea, or psychiatric
 illness/social situations that would limit compliance with study requirement,
 substantially increase risk of incurring AEs or compromise the ability of the patient
 to give written informed consent

 10. Proteinuria 3+ on dipstick analysis or >500 mg/24 hours

 11. Sodium or potassium levels > CTCAE v4.1 grade 1

 12. Current or prior use of immunosuppressive medication within 14 days before the first
 dose of durvalumab. The following are exceptions to this criterion:

 -  Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra
 articular injection)

 -  Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of
 prednisone or its equivalent

 -  Steroids as premedication for hypersensitivity reactions (eg, CT scan
 premedication)

 13. Female subjects who are pregnant or breastfeeding or male or female subjects of
 reproductive potential who are not willing to employ effective birth control from
 screening to 90 days after the last dose of durvalumab monotherapy.

 14. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
 excipients.

 15. History of allogeneic organ transplant

 16. Known history of previous clinical diagnosis of tuberculosis

 17. Active infection including tuberculosis (clinical evaluation that includes clinical
 history, physical examination and radiographic findings, and TB testing in line with
 local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
 hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients
 with a past or resolved HBV infection (defined as the presence of hepatitis B core
 antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
 hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
 for HCV RNA

 18. Renal failure requiring haemodialysis or peritoneal dialysis;

 19. Clinically unstable, active infection requiring systemic antibiotics;

 20. Concurrent cancer (except non-melanoma skin cancer or carcinoma in-situ of the
 cervix), unless in complete remission and off all therapy for that disease for a
 minimum of 3 years;

 21. Patients with significantly diseased or obstructed gastrointestinal tract,
 malabsorption, uncontrolled vomiting or diarrhea or inability to swallow oral
 medications.

 22. Patients with serious psychiatric or medical conditions that could interfere with
 treatment.

 23. Patients with prior MDS/ AML

 24. Require therapeutic doses of anti-coagulation with warfarin or warfarin derivatives.
 However, treatment with low molecular weight heparin (LMWH) is allowed.

 25. Brain metastases or spinal cord compression unless asymptomatic, treated and stable
 off steroids and anti-convulsants for at least 1 month prior to entry into the study

 26. Concurrent therapy with approved or investigational anticancer therapeutics;

 27. Receipt of live attenuated vaccination within 30 days prior to study entry