Does Cediranib Prevent Bowel Perforation in Platinum-resistant Ovarian Cancer

Ovarian cancer is the fourth most common cause of female cancer death and the commonest cause of gynaecological cancer death, accounting for 4,000 lives a year in the UK and 22,000 in the United States (1,2). The most common cause of death is malignant bowel obstruction, which occurs because of tumour physically and neurologically arresting bowel function (3).

New treatment strategies are required to address malignant bowel obstruction, which usually occurs in patients whose disease has become resistant to platinum-based chemotherapy. Several studies have reported higher response rates and increased PFS when a VEGF pathway inhibitor is combined with cytotoxic therapy in the first line (4,5), platinum-sensitive (6,7) and platinum-resistant recurrent disease settings (8). In the AURELIA study, the addition of the anti-angiogenic, monoclonal anti-VEGF antibody, bevacizumab, to physician's choice of cytotoxic agent significantly improved PFS. However, this study excluded patients who had received more than three previous regimens of treatment and those with clinical or radiological features of bowel obstruction on the basis that previous data had shown that the administration of bevacizumab to patients with prior bowel surgery, pelvic disease involving the recto sigmoid or symptoms of bowel obstruction would significantly increase the risk of bowel perforation(9), which can be fatal.

The above data demonstrate that there is an unmet need for a VEGF inhibitor that can be safely combined with cytotoxic therapy, which would increase the response rate and PFS in this population. The MITO-11 study demonstrated the safety and potential efficacy of the combination of pazopanib with weekly paclitaxel in platinum resistant disease (11) and the investigators have demonstrated in the in-house trial of cediranib with radiotherapy in colorectal cancer (DREAM trial; manuscript in preparation) that cediranib is effective and safe in the context of significant bowel wall disease, where bevacizumab has been previously reported to induce significant toxicity (12,13).

Taking these findings together, there is a strong rationale to develop a safe VEGF inhibitor-combination regimen in the setting of patients at risk of subacute bowel obstruction from ovarian cancer. Here, the investigators will evaluate the safety and efficacy of the potent VEGF receptor tyrosine kinase inhibitors (RTKi), cediranib, with weekly paclitaxel/nab-paclitaxel in women who are at risk of developing malignant bowel obstruction from ovarian cancer; a population in which bevacizumab is contra-indicated. Any risk to the patient's bowel will be minimized by bringing the abdominal disease under control with weekly paclitaxel /nab-paclitaxel for 1-3 cycles (3-9 weeks) before introducing the combination of paclitaxel/nab-paclitaxel with cediranib.

There is a critical need to develop effective and safe treatment regimens for patients with subacute bowel obstruction from ovarian cancer. Several trials have demonstrated the clinical benefit of adding bevacizumab to cytotoxic therapy in various settings in the disease yet in sub-acute bowel obstruction or in moderately heavily pre-treated patients, the antibody is contra-indicated due to the risk of bowel perforation or fistula.

Several findings suggest that VEGF RTKi are safer than antibodies in the presence of bowel dysfunction while preserving the efficacy advantage of the combination regimen. Here, we will evaluate the safety of the potent VEGF RTKi, cediranib, in combination with weekly paclitaxel in a cohort of patients at risk of developing malignant bowel obstruction, for whom bevacizumab is contraindicated.

Paclitaxel will be administered in CEBOC at 80mg/m2/week on days 1, 8 and 15 of a 3 week schedule, where the plan will be for patients to receive 6 cycles of treatment. The treatment is being given on a continuous weekly schedule in the same way that paclitaxel was prescribed in two large randomised trials of paclitaxel with a VEGF inhibitor. In one trial the VEGF inhibitor was the monoclonal anti-VEGF antibody, bevacizumab (14) and in the other, the VEGF receptor tyrosine kinase inhibitor, pazopanib was used (15). These two trials demonstrated that weekly paclitaxel can be safely and effectively combined with a VEGF inhibitor. However, the pazopanib trial, which involved administration of a VEGF inhibitor of the same class as cediranib, reported that 30% of patients incurred grade 3 or 4 neutropenia yet the investigators had restricted entry to the study to patients who had only received up to 3 previous lines of treatment. In CEBOC, patients can have received any number of previous lines of treatment and therefore to mitigate the risk of neutropenia, the trial involves the prescription of paclitaxel (16) at 70mg/m2/week rather than the slightly higher dose used in these two trials. As there is no evidence of a dose-response effect beyond standard doses of paclitaxel, the proposed regimen of 70mg/m2/week remains a standard of care.

The dose of cediranib selected for CEBOC is 20mg/day, which was biologically and clinically active in early phase clinical trials (17). Early attempts to combine cediranib with cytotoxic chemotherapy using a dose of the former at 30mg/day proved intolerable and therefore the standard combination dose of cediranib in recurrent ovarian cancer was 20mg/day.

Once patients in CEBOC have completed a maximum of 18 weeks of treatment with paclitaxel, those who have stable disease or better can continue taking cediranib alone at 20mg/day; again a dose that was used as maintenance therapy in ICON6 (18). At the point of developing progressive disease in CEBOC patients will need to fulfil another set of eligibility criteria but if they remain eligible, they can then supplement the cediranib with olaparib. The reason that the cediranib dose will remain 20mg/day in this component of CEBOC is because the phase II trial that described the activity of the combination (19) initially involved administration of a dose of cediranib 30mg/day but this had to be reduced in 77% of patients to 20mg/day. Given the amount of previous treatment the patients will have received at this point in CEBOC it is appropriate to use the more tolerable dose of cediranib, namely 20mg/day.

In CEBOC, patients who develop progressive disease while taking cediranib and who remain eligible to continue in the trial, will be prescribed olaparib tablets 300mg bd in addition to cediranib 20mg/day. The original formulation of olaparib was as 50mg capsules and the dose of capsules was 400mg bd. As the capsules only contained 50mg olaparib, the number of capsules patients had to take was considerable. Because of this, a tablet formulation of olaparib was developed, which resulted in the same exposure to olaparib when 300mg tablets twice daily were compared with capsules at 400mg twice daily, yielding similar clinical efficacy and toxicity while reducing the pill burden to four 150mg tablets per day (20).

The recommended monotherapy tablet dose of 300mg bd has now been evaluated as maintenance therapy in BRCA-mutation associated platinum-sensitive ovarian cancer in a placebo-controlled randomised phase 3 trial (21) where it demonstrated similar efficacy to that reported for the capsule formulation in the initial seminal randomised phase II trial which resulted in EMEA approval for olaparib (7,18).

A further phase II trial confirmed that the all-tablet cediranib-olaparib combination was associated with toxicities consistent with those observed when olaparib capsules were given in combination with cediranib (22). This study established two acceptable options for phase II dosing; either cediranib 20 mg once daily and olaparib 300 mg twice daily, or cediranib 30 mg once daily and olaparib 200 mg twice daily. Based on the earlier combination study showing that a high proportion of cediranib dose reductions were required from a starting dose of 30 mg once daily (19), therefore for the purpose of this trial, participants will receive cediranib 20 mg once daily and olaparib tablets 300 mg twice daily. Intensive symptom management guidelines will also be applied within this trial.

Inclusion criteria

Prior to paclitaxel and cediranib

• Histologically confirmed, progressive, platinum-resistant or refractory, high-grade ovarian, fallopian tube or primary peritoneal cancer for which weekly paclitaxel would be a potential treatment option
• Aged 16 years or over
• At risk of bowel obstruction: features compatible with this include increasing abdominal pain and swelling, borborygmi, change in bowel habit, extensive serosal disease or dilated or tethered bowel on radiological investigation. One or more of these should be present in eligible patients. Previous bowel obstruction is permitted providing patients can take oral medication and there is no concern about absorption of oral medication. Recto sigmoid involvement is permitted
• Adequate haematological function: Hb ≥ 100 g/l, Neutrophils ≥ 1.5 x 109/l, Platelets ≥ 100 x 109/l; coagulation: INR <1.4 (unless therapeutically anti-coagulated) and/or APPT ratio <1.4
• Adequate renal function defined as GFR ≥50ml/min and Creatinine clearance ≥50 mL/min using modified Wright or Cockcroft-Gault formula
• Adequate liver function: bilirubin ≤ 1.5 x ULN, transaminases ≤ 3 x ULN
• Any number of previous anti-cancer treatments permitted including weekly paclitaxel in the first-line setting
• Controlled hypertension permitted. Patients must have a blood pressure (BP) of ≤ Systolic BP (SBP):150/ Diastolic BP (DBP) 90 mmHg, with or without anti-hypertensive medication. BP measurements must be taken in the clinic setting by a medical professional within 2 weeks prior to starting study. A maximum of 3 anti-hypertensive medications are permitted and it is strongly recommended that patients who are on 3 anti-hypertensive medications be followed by a cardiologist or a primary care physician for management of BP while on study
• ECOG performance status 0-2 and life expectancy of over 12 weeks.
• Adequately controlled thyroid function, with no symptoms of thyroid dysfunction
• Measurable disease by RECIST v1.1
• Previous bevacizumab is permitted but patients cannot have been treated with VEGF RTKi previously
• Written informed consent
• Able to swallow and retain oral medications and without gastrointestinal (GI) illnesses that would preclude absorption of cediranib or olaparib.

Inclusion criteria

Prior to switching to olaparib and cediranib

• Radiological evidence of PD that is measurable per RECIST v1.1
• Meet inclusion criteria listed previously as points: 4-6, 8-10, 14
• No contra-indications to receive cediranib or olaparib.

Exclusion criteria

Prior to paclitaxel and cediranib

• Patients with a known hypersensitivity to olaparib, cediranib or paclitaxel or any of the excipients of the products
• Concurrent medical illness that would impact on compliance with the protocol including myelodysplastic syndrome (MDS)/ acute myeloid leukaemia (AML) or with features suggestive of MDS/AML
• Uncontrolled brain metastases or seizures. A scan to confirm the absence of brain metastases is not required. Central nervous system metastases:

• Symptomatic uncontrolled brain metastases requiring corticosteroid treatment
• History of spinal cord compression unless after definitive treatment the patient has clinically stable disease (SD) for at least 28 days prior to starting IMPs. In the absence of these features and in an asymptomatic patient a scan to confirm the absence of brain metastases is not required
• Known positivity for Hep B, Hep C or HIV
• Resting ECG with QTc > 470msec on 2 or more time points within a 24-hour period or family history of long QT syndrome
• Concomitant use of known strong CYP3A4/5 inhibitors such as such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir. Concomitant use of inducers or inhibitors (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) is also excluded. The required washout period prior to starting olaparib is 2 weeks
• Concomitant use of known strong (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 olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
• Another cancer, which has been active within the previous 5 years, except for adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin and no evidence of recurrence of other malignancy.
• Pregnant or lactating. Pregnancy status in women of child bearing potential will be confirmed via a serum or urine pregnancy test prior to randomisation, monthly during the treatment period, and at the end of treatment assessment. In addition, women of child bearing potential MUST be willing to ensure they use effective contraception for four weeks before entering the trial, throughout the treatment period and for six months following the end of treatment. Acceptable methods of contraception are:

i. true sexual abstinence (when this is in line with the preferred and usual lifestyle of the participant) ii. a combination of male condom plus one of:

• vasectomised sexual partner, with participant assurance that partner received post-vasectomy confirmation of azoospermia
• Tubal occlusion
• Intrauterine device provided coils are copper-banded
• Etonogestrel implants (eg, Implanon®, Norplant®)
• Normal and low dose combined oral pills
• Hormonal shot or injection (eg, Depo-Provera)
• Intrauterine system device (eg, levonorgestrel-releasing intrauterine system -Mirena®)
• Norelgestromin/ethinyl estradiol transdermal system
• Intravaginal device (eg, ethinyl estradiol and etonogestrel)
• Cerazette (desogestrel). Cerazette is currently the only highly efficacious progesterone based pill.
• Patients who are planning to receive maintenance bevacizumab
• Radiotherapy, surgery or tumour embolization within 28 days before the first dose of cediranib
• Additional concurrent anti-cancer therapy
• Malabsorption e.g. uncontrolled diarrhoea or poorly controlled stoma
• Previous or concurrent leukoencephalopathy, recent (within the past 6 months) arterial thromboembolic event (MI/CVA within previous 6 months), previous or concurrent fistula, previous or concurrent GI perforation, concurrent intra-abdominal abscess, previous VEGF RTKi or clinically relevant proteinuria
• Inability to comply with the protocol
• Major surgery within two weeks of starting study treatment and patients must have recovered from any effects of any major surgery
• Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, unstable angina, recent (within 6 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, resting ECG with clinically significant abnormal findings, NYHA grade III/IV cardiac failure, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent. 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 treatment with anthracyclines- except liposomal doxorubicin, which is permitted
• Prior treatment with trastuzumab
• Prior central thoracic RT, including exposure of heart to therapeutic doses of ionizing RT
• History of myocardial infarction within 6-12 months prior to start of IMPs
• Prior history of other significant impaired cardiac function
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
• Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
• Persisting ≥Grade 2 CTCAE toxicity (except alopecia and Grade 2 peripheral neuropathy) from previous anti-cancer treatment(s)
• Prior allogeneic bone marrow transplant or double umbilical cord blood transplantation.

Exclusion criteria

Prior to switching to olaparib and cediranib

• Meet exclusion criteria listed previously as points: 1-7, 9-11, 13-18, 20-21.