Cervical cancer is the 4th most prevalent female cancer worldwide. In the UK there are around
3,207 new cases each year (2013) and 890 deaths (2012)
(http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-t
ype/cervical-cancer). It is the most common cancer in females under 35 with the majority of
cases diagnosed in women aged 25-64. There is a large unmet need for active treatments in
metastatic and recurrent cervical cancer patients. Although early-stage and locally advanced
cancers may be cured with radical surgery, chemoradiotherapy or both, there are limited
options for patients with metastatic disease or persistent/ recurrent disease after
platinum-based chemoradiotherapy. Patients treated with chemotherapy for metastatic or
relapsed cervical cancer respond poorly to conventional chemotherapy (overall response rate
[ORR] of 30-35%) with a median overall survival of less than a year. The recent publication
of a phase III randomised controlled trial GOG 240 demonstrating a 3.7 month improvement in
median overall survival with the addition of bevacizumab to combination chemotherapy has
offered some hope for these patients. The ORR and progression free survival (PFS) were also
improved in patients receiving bevacizumab compared to those receiving chemotherapy alone.
The advantage seen with bevacizumab persisted in some subsets of patients including those
aged 48-56 years, and those with recurrent /persistent disease. Bevacizumab was also
effective in patients who had undergone pelvic irradiation. This was the first time a
targeted agent had significantly improved OS in gynaecological cancer.
High tumour angiogenesis is associated with poor survival when cervical cancer is treated
with radiotherapy and high tumour vascularity is a significant prognostic factor independent
of tumour radiosensitivity. A relationship between vascular endothelial growth factor (VEGF)
expression and OS has been demonstrated in patients treated with radiotherapy, and a review
of multiple biomarker studies in cervix cancer has highlighted the importance of VEGF as an
adverse prognostic factor. Targeting VEGF in cervical cancer may potentially exploit the role
of human papilloma virus (HPV, particularly subtypes 16 and 18) in the causation of cervical
cancer. The role of HPV in oncogenesis relates to the E6 and E7 proteins, with the former
promoting degradation of p53 while E7 inactivates retinoblastoma protein. Degradation of p53
may be responsible for activation of angiogenesis through production of VEGF and
downregulation of a potent angiogenesis inhibitor, thrombospondin.
Cediranib is a highly potent inhibitor of the tyrosine kinase activity of VEGF receptors 1-3
(VEGFR 1-3.) The recently published CIRCCa study demonstrated an increased PFS, VEGF-R
receptor inhibition and response rate with the addition of cediranib to carboplatin and
paclitaxel chemotherapy. This was accompanied by a manageable increased toxicity
(specifically diarrhoea and hypertension) with no detriment to QOL. The median PFS was
35weeks and 29 weeks in the cediranib and placebo arms respectively (HR 0.58 p= 0.032).
Understanding which patients are most likely to derive benefit from these agents requires
further evaluation as a priority.
Poly (ADP-ribose) polymerase (PARP) inhibitors including Olaparib may have potential activity
in cancers deficient in DNA repair genes or signalling pathways that mitigate DNA repair.
PARP inhibitors have demonstrated selectivity for cells harbouring homologous recombination
(HR) deficiencies such as those with BRCA mutations. HR deficient cells are unable to
maintain genomic integrity in the presence of large numbers of DNA DSBs and are therefore
sensitive to PARP inhibition. The activity of PARP inhibitors in not limited to those with
BRCA mutations and may demonstrate synthetic lethality in cancers deficient in other proteins
mitigating DNA repair, such as those with mutations in Fanconi anaemia complementation group
(FANC) proteins. Thus synthetic lethality may be more broadly applied to cancers with an
impaired HR pathway.
It is well recognised that persistent genital infection with high risk strain(s) of HPV is
necessary for the development of cervical cancer. Cells expressing high risk HPV oncoproteins
(E6 and E7, see above) demonstrate increased levels of DNA damage and chromosomal
instability, which may be a consequence of replicative stress; a process which is associated
with a number of cancer-prone syndromes. There is also evidence that HPV oncoproteins inhibit
the activation of DNA repair checkpoints, promote inappropriate DNA repair checkpoint
recovery and inhibit the activation of DNA repair mechanisms.
Current therapeutic modalities for cervical cancer exploit the sensitivity of these tumours
to DNA damaging agents such as ionising radiation and platinum chemotherapeutic agents. Poly
(ADP-ribose) polymerase (PARP) inhibitors reduce the DNA repair capacity of cells and can
induce synthetic lethality in cancers with underlying defects in DNA repair mechanisms such
as BRCA mutations (Scott, Swisher, and Kaufmann 2015). The investigators therefore postulate
that the action of HPV oncoproteins will lead to increase rates of DNA damage and reduced
efficiency of DNA repair, leading in turn to increased susceptibility to PARP inhibitors.
Inclusion Criteria:
- Patients over 18 years of age
- Histologically proven carcinoma of the cervix (squamous, adenocarcinoma or mixed
adeno/squamous).
- Completion of first line platinum-based chemotherapy for advanced /recurrent disease,
leading to either a complete response, partial response or stable disease.
- ECOG performance status 0 or 1
- Randomisation within 8 weeks of completion of chemotherapy
- Patients may have received previous chemoradiotherapy and neoadjuvant chemotherapy
given with a curative intent.
- Creatinine Clearance ≥ 51mls/min
- Adequate haematological and biochemical function, as follows:
- Haemoglobin > 10g/dl (with no blood transfusion in the 28 days prior to randomisation)
Neutrophils > 1.5 x 109/l
- Platelets > 100 x 109/l
- Bilirubin < 1.5 x ULN
- ALT or AST/ SGOT < 3 x ULN (or ≤5 x ULN if hepatic metastases present)
- Alkaline Phosphatase < 3 x ULN (or ≤5 x ULN if hepatic metastases present)
- Adequate coagulation, as follows:
- Prothrombin ratio (PTR) / INR ≤ 1.5 or
- PTR / INR between 2.0 and 3.0 for patients on stable doses of anticoagulants
- Partial thromboplastin time <1.2 x control
- Life expectancy >12 weeks.
- Informed written consent
- Contrast enhanced computerised tomography (CT) scan or magnetic resonance imaging
(MRI) of the abdomen and pelvis and a CT scan of the chest within 28 days prior to
commencing randomisation (with RECIST 1.1)
- Adequately controlled thyroid function, with no symptoms of thyroid dysfunction
- Able to swallow and retain oral medications and without gastrointestinal (GI)
illnesses that would preclude absorption of cediranib or olaparib
Exclusion Criteria:
- Disease that is potentially treatable with exenterative surgery.
- Relapse confined to the pelvis after radical surgery in circumstance where
radiotherapy or chemoradiotherapy would be appropriate.
- More than one line of prior chemotherapy for advanced/recurrent disease. Neoadjuvant
chemotherapy is not counted.
- Prior treatment with anti-angiogenic agents (with the exception of bevacizumab given
as part of first line chemotherapy)
- Persisting ≥Grade 2 CTCAE from previous anti-cancer previous systemic anti-cancer
therapy except haematological toxicity (see inclusion criteria "Adequate
haematological function") and alopecia.
- History of other malignancy within the previous 5 years except for:
- Curatively treated basal cell or squamous cell carcinoma of skin; in situ cancer of
the cervix, ductal carcinoma in situ of the breast or stage 1, grade 1 endometrial
carcinoma.
- Curatively treated other solid tumors including lymphomas (without bone marrow
involvement) with no evidence of disease for ≥5 years prior to start of IMPs.
- Pregnant or lactating women.
- Fertile woman of childbearing potential not willing to use adequate contraception
(oral contraceptives, intrauterine device or barrier method of contraception in
conjunction with spermicidal jelly or surgically sterile) for the study duration and
at least six months afterwards
- Evidence of uncontrolled infection. (Defined as infection that cannot be resolved
readily with antibiotics prior to patient entry into the trial for example a pelvic
collection)
- History of pelvic fistulae.
- History of abdominal fistula that has been surgically corrected within 6 months of
starting treatment. Patient should be deemed low risk of recurrent fistula
- Sub-acute or acute intestinal obstruction.
- Major surgery within 28 days or anticipated while on study.
- Non-healing wound, ulcer or bone fracture.
- Active bleeding.
- History or evidence of thrombotic or haemorrhagic disorders.
- History of stroke or transient ischemic attack within 6 months
- Proteinuria > 1+ on dipstick on two consecutive dipsticks taken no less than 1 week
apart, unless urinary protein is <1.5g in a 24 hour period.
- Significant cardiovascular disease (arterial thrombotic event within 12 months,
uncontrolled hypertension, myocardial infarction or angina within 6 months, NYHA grade
2 or worse congestive cardiac failure, grade ≥ 3 peripheral vascular disease or
cardiac arrhythmia requiring medication). Patients with rate-controlled atrial
fibrillation are eligible.
- Prolonged QTc (corrected) interval of >470ms on ECG or a family history of long QT
syndrome.
- Patients with symptomatic uncontrolled brain or meningeal metastases CNS disease
(brain metastases, uncontrolled seizures or cerebrovascular accident/transient
ischaemic attack /subarachnoid haemorrhage within 6 months).
- (A scan to confirm the absence of brain metastases is not required)
- A history of poorly controlled hypertension or resting BP>140/90 mmHG in the presence
or absence of a stable regimen of anti-hypertensive therapy (measurements will be made
after the patient has been resting supine for a minimum of 5 minutes. Two or more
readings should be taken at 2 minute intervals and averaged. If the first two
diastolic readings differ by more than 5mmHG, then an additional reading should be
obtained and averaged).
- History of significant gastrointestinal impairment. Defined as active inflammatory
bowel disease, bowel obstruction or any condition judged by the investigator to
adversely impact on drug absorption or within 3 months prior to starting treatment.
- Patients with myelodysplastic syndrome/acute myeloid leukaemia.
- Evidence of any other disease, metabolic dysfunction, physical examination finding or
laboratory finding giving reasonable suspicion of a disease or condition that
contra-indicates the use of an investigational drug or puts the patient at high risk
for treatment-related complications.
- Patients who have been treated with potent inhibitors of CYP3A4 and 2C8 such as
amiodaraone, clarithromycin, erythromycin, simvastatin, atorvastatin, lovastatin,
montelukast sodium, verapamil, ketoconazole, miconazole, indinovir (and other
antivirals) and diltiazem within 2 weeks of the first planned dose of cediranib will
be excluded [NB These drugs are also prohibited during trial period]
- Patients treated with CYP3A inhibitors 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). Within 2 weeks of the first planned
dose for strong inhibitors, and at least 1 week for moderate inhibitors.
- Concomitant use of known strong CYP3A inducers (e.g., phenobarbital, enzalutamide,
phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's
Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required
washout period prior to starting study treatments is 5 weeks for enzalutamide or
phenobarbital and 4 weeks for other agents. [NB These drugs are also prohibited during
trial period]
- Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) per
institutional guidelines, or <55%, if threshold for normal not otherwise specified by
institutional guidelines, for patients with the following risk factors:
- prior anthracycline, trastuzumab , chest radiotherapy, history of myocardial
infarction within 6 months prior to start of study drug or other significant impaired
cardiac function within 6-12 months prior to start of IMPs
- Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or
HIV, or who are receiving immunosuppressive treatment (with the exception of stable
doses of steroids equivalent or less than prednisolone 10mg daily).
- History of intra-abdominal abscess within 3 months prior to starting treatment.
- Uncontrolled intercurrent illness including, but not limited to known ongoing or
active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, extensive interstitial bilateral lung disease on High Resolution
Computed Tomography (HRCT) scan or psychiatric illness/social situations that would
limit compliance with study requirements.
- Prior allogeneic bone marrow transplant or double umbilical cord blood transplantation
