Eligibility Details:
Inclusion Criteria:
- Signed informed consent
- Age ≥18
- ECOG 0-1
- Have histologically/cytologically-documented, locally-advanced, or metastatic mismatch
repair proficient colorectal cancer (MMRp-CRC), pancreatic adenocarcinoma (PA), or
leiomyosarcoma (LMS) that is incurable and has either (a) failed prior standard
therapy, (b) for which no standard therapy exists, or (c) standard therapy is not
considered appropriate by the subject and treating physician
- Allowable: prior immune-oncology therapy, no maximal limit to the number of prior
lines of systemic therapy for advanced or metastatic disease. All prior
anti-neoplastic systemic therapy, including immune-oncology, must have a 4 week wash
out period. There is no limit to the number of prior anti-neoplastic systemic
treatments used before trial enrolment
- Must have at least 1 tumor site that is amendable to tumor biopsy
- Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion. Newly-obtained is defined as a specimen obtained up to 4 weeks (28 days)
prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples
cannot be provided will not be eligible for this study. Subjects who have archival
tissue available, not older than 6 months and with no intervening therapies from the
day of the biopsy and the initiation of the study, will also be requested to also
submit this sample, but are still required to undergo a pre-treatment biopsy.
- Consent to provide archival tumor tissue for correlative biomarker studies
- Must have at least 1 tumor site that is RECISTv1.1 measurable by CT or MRI scan. A
previously irradiated lesion can be considered a target lesion if the lesion is well
defined, measurable and there is objective evidence of progression following
radiotherapy. The biopsy lesion cannot be the same as the target lesion
- Life expectancy ≥ 16 weeks from proposed first dose date
- Female subject of childbearing potential should have two negative pregnancy tests as
verified by the investigator prior to starting any investigational product therapy:
serum pregnancy test at screening and negative serum or urine pregnancy test on Cycle
1, Day 1 prior to treatment, and confirmed prior to each subsequent cycle of
treatment. If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required. They must agree to pregnancy testing after the last
dose of durvalumab, olaparib or cediranib. This applies even if the subject practices
complete abstinence from heterosexual contact
- Females of childbearing potential who are sexually active with a non-sterilized male
partner must agree to practice true abstinence or at least two effective methods of
contraception from 28 days prior to starting durvalumab, olaparib or cediranib, and
agree to continue using such precautions while taking durvalumab, olaparib or
cediranib and for 90 days following the last dose of investigational product(s).
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable
methods of contraception. They must also refrain from egg cell donation and
breastfeeding during study participation and for at least 90 days after the final dose
of investigational product(s)
- Non-sterilized males who are sexually active with a female partner of childbearing
potential must agree to use at least two effective methods of contraception from Day 1
through 90 days after receipt of the final dose of investigational product(s). In
addition, they must refrain from sperm donation for 90 days after the final dose of
investigational product(s). Female partners of male patients should also use a highly
effective form of contraception if they are of childbearing potential
- Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up
- Adequately controlled thyroid function, with no symptoms of thyroid dysfunction.
Elevated thyroid stimulating hormone (TSH) with normal free T3 and free T4 are
allowed; subjects on thyroid replacement therapy are allowed
- Patients must have normal organ and bone marrow function measured within 28 days prior
to administration of study treatment as defined below. Subjects are not allowed to
have received blood transfusion upwards of 28 days prior to study treatment
2.Cohort A
- Subjects with MMRp-CRC, PA or LMS with the presence or absence of DDR and HRR
(homologous recombination repair) genes will be evaluated retrospectively but it is
not an eligibility criterion. Prior PARP usage, including olaparib, is excluded, but
other DDR pathway inhibitors are allowed
3. Cohort B
- Prior antiangiogenic treatment is allowed.
Exclusion Criteria:
1. All cohorts
- Involvement in the planning and/or conduct of the study or previous enrolment in
the present study
- Subjects with another malignancy unless curatively treated with no evidence of
disease for ≥ 5 years except: adequately treated non-melanoma skin cancer,
curatively treated in situ cancer of the cervix, ductal carcinoma in situ, Stage
1, grade 1 endometrial carcinoma. Patients with a history of localized triple
negative breast cancer may be eligible, provided they completed their adjuvant
chemotherapy more than three years prior to registration, and that the patient
remains free of recurrent or metastatic disease
- Untreated central nervous system (CNS) metastatic disease, leptomeningeal
disease, or cord compression. Subjects with previously treated brain metastases
may participate provided they are stable, have no evidence of new or enlarging
brain metastases, and are not using steroids for at least 14 days prior to trial
treatment. This exception does not include carcinomatous meningitis which is
excluded regardless of clinical stability. Subjects with a history of treated
asymptomatic CNS metastases are eligible, provided they meet all of the following
criteria:
- Measurable disease outside the CNS
- Only supratentorial metastases allowed
- No history of intracranial hemorrhage
- No ongoing requirement for corticosteroids as therapy for CNS disease;
anticonvulsants at a stable dose allowed
- No stereotactic radiation within 7 days or whole-brain radiation within 14
days prior to Day 1 of the study
- No evidence of interim progression between the completion of CNS-directed
therapy and the screening radiographic study
- Participation in another clinical study with an investigational product during
the last 28 days or 5 half-lives prior to study Day 1. Concurrent enrolment in an
observational clinical study or the follow-up period of an interventional study
is allowed
- Subjects receiving any systemic chemotherapy, radiotherapy, within 4 weeks from
the last dose prior to study treatment.
- Receiving, or having received during the four weeks prior to study entry,
corticosteroids for any reason. The following are exceptions to this criterion:
- Intranasal, inhaled, topical, or local steroid injections
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or equivalent
- Steroids as premedication for hypersensitivity reactions
- Receipt of live attenuated vaccination within 30 days prior to study entry or
within 30 days of investigational products. Vaccination with a killed vaccine is
permitted at any time with consultation with the Principal Investigator
- Major surgery within 28 days prior to Day 1 of the study or still recovering from
prior surgery. Local procedures are allowed if completed at least 24 hours prior
to the administration of the first dose of study treatment
- Any unresolved toxicity NCI CTCAE v5.0 Grade ≥ 2 from previous anticancer therapy
with the exception of alopecia, vitiligo, hypothyroidism and the laboratory
values defined in the inclusion criteria
- Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis
after consultation with the Study Physician
- Patients with irreversible toxicity not reasonably expected to be
exacerbated by treatment by the investigation product may be included only
after consultation with the Study Physician
- Any prior unresolved NCI CTCAE v5.0 Grade > 1 irAE while receiving any previous
immunotherapy agent with exception of chronic endocrinopathy that is stable on
hormone replacement. Subjects who developed Grade 2 or 3 irAE that has since
resolved can be discussed with the Principal Investigator.
- Diagnosis of autoimmune-based rheumatologic disease or clinically significant
autoimmune disorders. Subjects with vitiligo, Grave's disease, or psoriasis not
requiring systemic treatment are not excluded. Subjects with hypothyroidism on
thyroid supplements are not excluded
- History of primary immunodeficiency
- Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation
- History of hypersensitivity to durvalumab, olaparib, cediranib or any excipient
- Measurable mean value QTcF > 470 msec on resting triplicate ECG within a 24 hour
period, or if resting ECG indicates uncontrolled, potentially reversible cardiac
conditions, or patients with congenital or family history of long QT syndrome
- Subjects with relative hypotension (< 100/60 mm Hg) or clinically relevant
orthostatic hypotension, including a fall in blood pressure of > 20mm Hg
- A history of poorly controlled hypertension or resting blood pressure > 150/100
mmHg in the presence or absence of a stable regimen of anti-hypertensive therapy
---Adequately controlled BP: systolic BP ≤ 140 mmHg and diastolic BP ≤ 90 mmHg in
the presence or absence of a stable regimen of antihypertensive therapy.
- Left ventricular ejection fraction < lower limit of normal (LLN) per
institutional guidelines, or <55%, if threshold for normal is not otherwise
specified by institutional guidelines, for patients with the following risk
factors:
- Prior or planned treatment with anthracyclines
- Prior treatment with trastuzumab
- Prior central thoracic radiation therapy (RT), including exposure of heart
to therapeutic doses of ionizing RT
- History of myocardial infarction within 6 to 12 months prior to
randomization
- Prior history of other significant impaired cardiac function
- Refractory nausea and vomiting, chronic gastrointestinal diseases or previous
significant bowel resection that would preclude adequate absorption of oral drugs
- History of bowel obstruction within 1 month prior to starting study drugs
- Subjects unable to swallow orally administered medication
- Subjects may not have current dependency on IV hydration or total parenteral
nutrition
- Subjects with uncontrolled seizures
- Active infection requiring systemic antibiotics, antifungal or antiviral drugs
- Any evidence of severe or uncontrolled systemic disease, active infection, active
bleeding diatheses or renal transplant, including any subject known to have
active tuberculosis, hepatitis B, hepatitis C or human immunodeficiency virus,
immunocompromised patients, or any patients with a psychiatric disorder that
prohibits obtaining informed consent. Subjects who have had adequately treated
tuberculosis may be enrolled upon discussion with Principal Investigators.
Subjects who have had prior hepatitis B and C and are not carriers, or have been
cured with antivirals, are eligible
- Female subjects who are pregnant, breast-feeding or male or female subjects of
reproductive potential who are not employing an effective method of birth control
- History of myocardial infarction within 6 months prior to registration
- History of stroke or transient ischemic attack within 6 months prior to
registration
- Heart failure class III or IV
- Current cardiac arrhythmia requiring concurrent use of anti-arrhythmic drugs
- History of hypertensive crisis or hypertensive encephalopathy within 3 years
prior to registration, or poorly controlled hypertension at time of registration
- Clinically significant peripheral vascular disease or abdominal aortic aneurysm
(> 5 cm) or aortic dissection. If known history of abdominal aortic aneurysm with
≥ 4 cm in diameter, all of the following must be met: an ultrasound within the
last 6 months prior to registration will be required to document that it is ≤ 5
cm; subjects must be asymptomatic from the aneurysm; blood pressure must be well
controlled as defined in this protocol
- Unstable angina within 6 months prior to randomization
- History of hemoptysis or any significant bleeding within the last 1 month prior
to enrollment
- Presence of cavitation of central pulmonary lesion
- History of abdominal fistula, intra-abdominal abscess, or gastrointestinal
perforation, within the 3 months prior to enrollment
- Subjects may not have history of bleeding diathesis or coagulopathy. Therapeutic
anticoagulation for prior thromboembolic events is permitted but must be
discussed with the PI. Subjects requiring two or more anti-thrombotic agents,
including anti-platelet agents will be excluded
- Any condition that would interfere with evaluation of study treatment or
interpretation of subject safety or study results.
- Subjects who are involuntarily incarcerated or are unable to willingly provide
consent or are unable to comply with the protocol procedures
- Subjects who require blood transfusion within 28 days prior to study entry to
maintain Hgb > 100 g/L or platelets > 100 x 109/L. Whole blood transfusions in
the last 120 days prior to entry to the study are acceptable, outside of 28 days
prior to treatment
2. Cohort A (olaparib, durvalumab)
- Concomitant use of known strong CYP3A inhibitors or moderate CYP3A inhibitors.
The required washout period prior to starting study treatment is 2 weeks
- Concomitant use of known strong or moderate CYP3A inducers . The required washout
period prior to starting study treatment is 5 weeks for enzalutamide or
phenobarbital and 3 weeks for other agents
- If clinically indicated, subjects may not have features suggestive of
myelodysplastic syndrome or acute myelogenous leukemia on peripheral blood smear
or bone marrow biopsy.
3. Cohort B (cediranib, durvalumab)
- A major surgical procedure, open biopsy, or significant traumatic injury within
28 days prior to starting cediranib
- Concomitant use of known strong cytochrome (CYP) 3A inhibitors or moderate CYP3A
inhibitors. The required washout period prior to starting study treatments is 2
weeks for strong inhibitors, and at least 1 week for moderate inhibitors
- Concomitant use of known strong CYP3A inducers or moderate CYP3A inducers. The
required washout period prior to starting study treatments is 5 weeks for
enzalutamide or phenobarbital and 4 weeks for other agents
common.study.methods.has-drugs-yes
common.study.methods.is-healthy-yes
