Phase II trial of olaparib in combination with ceralasertib in patients with recurrent osteosarcoma

This study is being done in order to evaluate the effectiveness of using two drugs
(olaparib and ceralasertib) to treat patients with osteosarcoma that has not responded to
treatment or has come back after treatment

The names of the study drugs involved in this study are:

- Olaparib

- Ceralasertib

Inclusion Criteria:

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

- Age > 12 years and ≤ 40 years

- Weight > 40 kg

- Lansky/Karnofsky performance status ≥ 60% for participants ≥16 years of age and
Lansky ≥ 60% for participants <16 years of age (see Appendix B) within 28 days prior
to enrollment with no deterioration over the previous 2 weeks. Please note, patients
who have had prior orthopedic surgery as part of their osteosarcoma therapy should
not be considered non-ambulatory in their performance status if their non-ambulatory
status is the result of surgery.

- Estimated life expectancy of ≥16 weeks.

- Diagnosis requirement

- All participants must have histologic verification of osteosarcoma at original
diagnosis or relapse

- All participants must have disease that has relapsed or has become refractory
to conventional therapy

- Cohort 1 Requirements

- Participants must have measurable disease according to RECIST v1.1. At least
one measurable lesion that can be accurately assessed at baseline by computed
tomography (CT) (magnetic resonance imaging [MRI] where CT is contraindicated)
and is suitable for repeated assessment as per RECIST v1.1.

- Surgical resection of all possible sites of disease is not feasible or will
result in major and / or unacceptable morbidity and no other standard of care
treatment is available per assessment of the treating investigator

- Participants must have archival tumor specimen available for submission.

- Cohort 2 Requirements

- Participants must have had at least one episode of disease recurrence currently
limited to the lung parenchyma with no limits on the number of episodes of
recurrence

- Surgical resection of all possible sites of suspected pulmonary metastases in
order to achieve a complete remission is considered feasible by treating
physicians

- Participants with pulmonary disease on only one side must have archival tumor
specimen available for submission.

- Participants must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy. Participants must meet the following minimum washout periods
prior to registration:

- Myeloid growth factors: At least 14 days following the last dose of long-acting
growth factor (e.g. Neulasta) or 7 days following short-acting growth factor.

- Stem Cell or Autologous T Cell Infusion: At least 42 days must have elapsed
after stem cell or autologous T cell infusion.

- Participants must not have previously received and progressed on olaparib or
other PARP inhibitor therapy.

- Participants must not have previously received and progressed on ceralasertib
or other ATR inhibitor therapy.

- Participants must have normal organ function as defined below.

- Bone Marrow Function

- Absolute neutrophil count ≥1,250/uL

- Platelets ≥100,000/uL (with no platelet transfusions within the last 28
days)

- Hemoglobin ≥9 g/dL (with no blood transfusion or erythpoetin use within
past 28 days)

- Hepatic Function

- Total bilirubin ≤ 1.5 x ULN unless the patient has documented Gilbert's
syndrome

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

- Renal Function

--- A serum creatinine based on age/gender as follows:

- Age Maximum Serum Creatinine (mg/dL)

- Age: 12 to <13 years Maximum Serum Creatinine (mg/dL): Male 1.2 Female 1.2

- Age: 13 to < 16 years Maximum Serum Creatinine (mg/dL): Male 1.5 Female1.4

- Age: ≥ 16 years Maximum Serum Creatinine (mg/dL): Male 1.7 Female 1.4 OR

- Creatinine clearance ≥ 70 mL/min/1.73 m2 for participants with creatinine
levels above institutional normal

- Participants must be able to swallow intact pills.

- Female participants must have a negative serum or urine pregnancy test within 28
days of study treatment and confirmed prior to treatment on Cycle 1 Day 1.

- Females must not be breast feeding. Women of childbearing potential and their
partners, who are sexually active, must agree to the use of 2 highly effective forms
of contraception in combination from the signing of the informed consent, 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 who are sexually active must be willing to use barrier contraception
for the duration of the study and for 1 week after the last study drug
administration, with all sexual partners. Male patients must use a condom during
treatment and for 6 months after the last dose of study drug(s) when having sexual
intercourse with a pregnant woman or with a woman of childbearing potential and must
not donate sperm for 6 months after the last dose of study drug. Female partners of
male patients should also use a highly effective form of contraception for 6 months
after the last dose of study drug(s) if they are of childbearing potential. True
abstinence for either sex is an acceptable form of contraception and must be
documented as such.

- Ability to understand and/or the willingness of the patient (or parent or legally
authorized representative, if minor) to provide informed consent, documented using
an institutionally approved informed consent procedure.

- Patient is willing and able to comply with the protocol for the duration of the
study including undergoing treatment and scheduled visits and examinations.

Exclusion Criteria:

- Participants with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) or
features suggestive of MDS/AML.

- Patients with a known diagnosis of ataxia telangiectasia.

- Cytotoxic chemotherapy, hormonal or non-hormonal targeted therapy within 21 days of
Cycle 1 Day 1 is not permitted (a duration of five half times is allowed for
patients treated with noncytotoxic drugs).

- Immunotherapy within 42 days of Cycle 1 Day 1.

- Prior TOTAL lung radiation. If prior radiation included lung then radiation must
have been completed 12 weeks before Cycle 1 Day 1 AND V20 (% of lung that received
20Gy) must not exceed 25% OR the mean lung dose must be less than 5Gy. Even if these
eligibility criteria are met, patients who have received prior radiotherapy
including lung are only eligible after review and approval by the study PI.

- Palliative radiotherapy to sites not including lung must have been completed 7 or
more days before Cycle 1 Day 1 (with the following exception: patients receiving
radiation to more than 30% of the bone marrow or with a wide field of radiation must
have been completed 4 weeks before C1D1. The patient can receive a stable dose of
bisphosphonates or denosumab for bone metastases, before and during the study as
long as these were started at least 5 days prior to the study treatment.

- Receiving, or having received during the 14 days prior to Cycle 1 Day 1,
corticosteroids (at a dose > 10 mg prednisone/day or equivalent) for any reason.
Topical, inhaled or ophthalmic steroid administration is acceptable.

- Major surgery within 2 weeks of starting study treatment: patients must have
recovered from any effects of any major surgery.

- Any other malignancy which has been active or treated within the past three years,
with the exception of cervical intra-epithelial neoplasia and non-melanoma skin
cancer, Ductal Carcinoma in Situ, stage 1 grade 1 endometrial carcinoma, or other
solid tumors curatively treated with no evidence of disease for ≥ 5 years prior to
study entry.

- With the exception of alopecia and CTCAE grade 2 neuropathy, any unresolved
toxicities from prior therapy ≥ Common Terminology Criteria for Adverse Events
(CTCAE) grade 2.

- Patient with resting left-ventricular ejection fraction (LVEF) < 50% measured by
ECHO/MUGA

- Any of the following cardiac diseases currently or within the last 6 months (by New
York Heart Association (NYHA) ≥ Class 2 where applicable):

- Unstable angina pectoris

- Congestive heart failure or known reduced LVEF < 50%

- Acute myocardial infarction

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

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

- Patients at risk of brain perfusion problems, e.g., medical history of carotid
stenosis or pre-syncopal or syncopal episodes, history of TIAs

- Uncontrolled hypertension (grade 2 or above) requiring clinical intervention

- Corrected QT interval (QTc) > 470msec obtained from 3 electrocardiograms (ECGs) 2-5
minutes apart using the Fredericia formula

- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as congestive heart failure, unstable angina pectoris, acute
myocardial infarction, hypokalaemia, congenital long QT syndrome, immediate
family history of long QT syndrome or unexplained sudden death under 40 years
of age, conduction abnormality not controlled with pacemaker or medication.

- Patients with relative hypotension (less than 5th percentile for age/height/sex or
systolic and/or diastolic blood pressure >15% below baseline) or clinically relevant
orthostatic hypotension (a fall in systolic blood pressure of at least 20 mm Hg
within 3 minutes of standing compared to blood pressure obtained from sitting/supine
position).

- Concomitant use of known potent cytochrome P (CYP) 3A inhibitors (eg.itraconazole,
telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or
cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate
CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole,
verapamil). The required washout period prior to starting study treatment is five
half-lives.

- Concomitant use of known potent (eg. phenobarbital, enzalutamide, phenytoin,
rifampicin,rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort)
CYP3A inducers (eg.bosentan, efavirenz, modafinil). The required washout period
prior to starting study treatment is five half-lives, except for St-Johns' wort,
which is 3 weeks.

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 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 E for further details.

- Planned herbal medications use within 7 days prior to first dose of study treatment.

- Refractory nausea and vomiting, chronic gastrointestinal diseases or previous
significant bowel resection, with clinically significant sequelae that would
preclude adequate absorption of ceralasertib.

- Participants with a known hypersensitivity to olaparib or any of the excipients of
the product or any contraindication to the combination anti-cancer agent as per
local prescribing information.

- Participants with a known hypersensitivity to ceralasertib or any of the excipients
of the product or any contraindication to the combination anti-cancer agent as per
local prescribing information.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance
with study requirements.

- 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, 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.

- Patients with symptomatic uncontrolled brain metastases. Patients with a history of
treated central nervous system (CMS) 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 CNSdirected therapy, minimum 3 weeks between
completion of radiotherapy and Cycle 1 Day 1 and recovery from significant (Grade ≥
3) acute toxicity with no ongoing requirement for >10 mg of prednisolone per day or
an equivalent dose of other corticosteroid. If on corticosteroids, the patient
should be receiving a stable dose of corticosteroids, started at least 4 weeks prior
to treatment.

- Female patients who are pregnant or breast-feeding.

- Male or female patients of reproductive potential who are not employing an effective
method of birth control.

- Spinal cord compression or brain metastases unless treated, asymptomatic and stable
and not requiring steroids for at least 4 weeks prior to start of study treatment.