Michael Gonzalez, Khurum Khan, and Bristi Basu
Case history
A 52-year-old woman with stage IIIC high-grade serous-papillary ovarian cancer was referred for consideration of further management having received six lines of treatment over 6 years, including weekly paclitaxel and liposomal doxorubicin, for what had become platinum-resistant disease. A reassessment CT scan showed an increase in the size of her peritoneal lesions with a pelvic mass of 6cm that remained unchanged. Her CA-125 levels had risen ten-fold in 6 weeks from a nadir of 50U/ml (normal <35U/ml). She was asymptomatic. Past medical history included insulin-requiring type 2 diabetes mellitus, an acute myocardial infarction, and essential hypertension. Vascular access was problematic during her last chemotherapy. Since then, she required anticoagulation with low-molecular-weight heparin for a catheter-associated deep-vein thrombosis of the left arm.
Questions
1. What are the treatment options available for this patient?
2. What features of the patient and her disease would it be important to know about in order to consider entry into a phase I study?
3. How should this patient be assessed for eligibility?
Answers
1. What are the treatment options available for this patient?
In view of the platinum-resistant disease and progression after six lines of systemic treatment, this patient no longer has chemosensitive disease. She is asymptomatic but likely to soon encounter complications from disease progression. Options are limited at this stage and good supportive and palliative care is paramount.
Entry into a clinical trial should be considered following careful evaluation. Phase I clinical studies are drug trials that involve the introduction of compounds into patients, either as single agents or combinations, after they have undergone careful pre-clinical evaluation through laboratory experiments in cultured cells and animals (as an initial toxicology screen and to calculate a starting dose). As they may be ‘first-in-human’ studies, these early phase clinical studies aim to assess safety and tolerability in order to determine a recommended dose to take to phase II trials. Phase II studies then provide an initial assessment of efficacy, subsequently assessed in a randomized setting during a phase III trial. Phase IV clinical studies aim to identify an unexpected toxicity that is likely to be uncommon but potentially serious. However, having had several lines of conventional therapy already, the options of phase II and phase III clinical trials are limited, as in this context standard therapies are quite often compared with the trial medication. Many of these studies also preclude patients who have already received several lines of treatment.
2. What features of the patient and her disease would it be important to know about in order to consider entry into a phase I study?
Specific eligibility criteria should be sought for any individual trial according to those stipulated in published protocols. In general, the following parameters need to be considered:
♦ Performance status: most studies would require patients to have an ECOG performance status of 0 or 1 at study entry. This patient is asymptomatic and likely to be leading an active life, which is permissive for entry into a clinical study.
♦ Current symptoms: symptom control should be optimized prior to study entry, for example nausea and vomiting should be controlled before starting an oral drug trial.
♦ Adequate organ function: depending on how the drug is metabolized, screening for organ dysfunction is required. Organ impairment is likely to affect the safety and tolerability of trial medication, and is particularly important when toxicities of the agent under investigation may worsen organ function.
♦ Comorbidities: patients with serious and uncontrolled comorbidities, or active infection, are generally excluded from phase I trials. Specific medical conditions might also exclude patients from certain clinical trials, e.g. a patient with a history of arrhythmias or QTc interval prolongation should be precluded from studies on drugs which may have shown a pre-clinical effect on human Ether-à-go-go-Related Gene (hERG) potassium ion channels.
♦ Potential drug interactions: there is a risk of increased toxicity or diminished drug efficacy with cytochrome P450 (CYP) liver enzymes that are induced or inhibited by concomitant medications.
♦ Vascular access: many of the novel drugs under investigation are oral agents, but vascular access may still need to be considered since patients on many trials have to provide serial blood samples, e.g. for pharmacokinetic analysis.
♦ Disease amenable to biopsy: to determine the pharmacodynamic modulation of signalling pathways or to assess treatment efficacy by laboratory analysis of the sampled tissue if this is safe to acquire.
♦ Expected survival of more than 3 months: this is a generally accepted eligibility criterion for most patients entering a clinical study.
♦ Patient commitment, but realism: patients can be desperate to continue to be actively managed and treated. They can be desperate not to give up. This patient is very likely to be in this category as she has previously had six lines of treatment and is asymptomatic. However, phase I treatment has no proven efficacy and may just give toxicity and adversely affect her quality of life.
3. How should this patient be assessed for eligibility?
A screening visit is part of the assessment in many clinical trials. At this clinical review, a full history is obtained and physical examination is performed. Careful documentation is important since symptoms and signs that are present at baseline need to be recorded and monitored during the course of the study. Investigations may include:
♦ Blood tests, including tumour markers to establish that there is biochemical progression, and system-specific investigations to assess organ function. For example, respiratory investigations might involve full lung function tests, whereas cardiac investigations might include an ECG, echocardiogram, MUGA, or Holter monitoring.
♦ Imaging to confirm the presence of radiological progression. Measurable disease, however, is not always a requirement for clinical trials.
This patient enters a phase III clinical trial evaluating the role of bevacizumab, an anti-VEGF agent, but withdraws from the trial after one infusion because of worsening of pre-existing hypertension. Meanwhile, her daughter, aged 22, is diagnosed with an operable invasive ductal carcinoma of the left breast.
Questions
4. What is the significance of her daughter’s new diagnosis?
5. How might this new information influence further management for the patient?
Answers
4. What is the significance of her daughter’s new diagnosis?
A thorough family history is important to exclude the possibility of an inherited malignancy. In this case, the occurrence of breast cancer in a first-degree young relative of a patient with ovarian cancer should prompt referral to a specialist in cancer genetics for an assessment to identify whether a germline mutation of the BRCA gene is present. Mutations in the two BRCA genes, BRCA1 and BRCA2, can be of autosomal dominant inheritance but the penetrance is frequently variable between generations. Affected women are at risk of developing ovarian cancer, affected men have a higher risk of prostate cancer, and both genders are at increased risk of developing breast and pancreatic cancers.
5. How might this new information influence further management for the patient?
Tumours in patients who harbour germline mutations of BRCA1 or BRCA2 may show increased sensitivity to treatment with poly-ADP ribose polymerase (PARP) inhibitors. BRCA deficiency results in defective homologous recombination repair of damaged DNA. Therefore cancer cells within tumours arising in a BRCA-deficient context are dependent on PARP enzymes which are required for the salvage DNA repair pathway. The observation that single-agent PARP inhibitors could preferentially target cancers harbouring defects in homologous recombination repair of DNA, to achieve profound cytotoxicity within the tumour whilst sparing normal tissue, has provided the first therapeutic example of ‘synthetic lethality’. The selective effect of PARP inhibition with drugs such as olaparib (AZD2281) can be observed as a clinical, radiological, and biochemical response in patients who carry a BRCA mutation. The main toxicities of olaparib are nausea, fatigue, and bone marrow suppression, primarily thrombocytopenia. At present, however, PARP inhibitors are not licensed and are only available by enrolment of eligible patients into a clinical study.
The patient commences treatment on a phase I clinical study investigating a novel PARP inhibitor.
Questions
6. What are the aims of a phase I clinical study?
7. What useful parameters are monitored during the course of a phase I study?
8. What factors in the patient history might predict clinical outcome?
9. What other options are available to this woman if she progresses?
Answers
6. What are the aims of a phase I clinical study?
A phase I study is to determine the safety and tolerability of a novel agent or drug combination, as well to establish the dose-limiting toxicity (i.e. the toxicity that is considered unacceptable because of severity and/or irreversibility, limiting further dose escalation). Phase I studies will further indicate the maximum tolerated dose of the trial drug, defined as the highest dose of a treatment that does not cause unacceptable side-effects. Toxicities are recorded using standardized grading criteria, such as the National Cancer Institute (NCI) common toxicity criteria (CTC). Dose-limiting toxicity usually corresponds to NCI CTC grade 3 or grade 4. Preliminary evidence of objective antitumour activity is also reported in phase I studies, for further evaluation in a phase II clinical trial.
7. What useful parameters are monitored during the course of a phase I study?
During a phase I study, and frequently prior to entry, patients provide regular samples of blood and tissue. Frequent visits are required during the early parts of the study when the patient has commenced regular dosing to monitor for toxicities from the trial drug.
Pharmacokinetic tests involve serum assays of blood levels to determine ‘what the body does to the drug’ in terms of absorption, distribution, metabolism, and excretion. Parameters that are usually defined include the maximum concentration of the drug (Cmax), exposure to the drug (calculated from the area under the curve or AUC), its half-life (t½), and clearance.
Pharmacodynamic testing investigates ‘what the drug does to the body’, for example in terms of nadir counts observed, non-haematological toxicity, molecular correlates of drug inhibition, and imaging end-points such as reduced FDG uptake on PET-CT.
8. What factors in the patient history might predict clinical outcome?
Patient selection for phase I clinical studies can be challenging, because although a predicted life expectancy of more than 3 months is required, accurate assessment of life expectancy is difficult in patients with advanced and treatment-refractory cancer. Performance status can help predict clinical outcome but remains a subjective assessment. The Royal Marsden Hospital prognostic score has been developed and validated as a helpful guide for appropriate patient selection based on a predicted 90-day mortality. To calculate a score out of 3 (minimum 0, maximum 3), one point is added for each of the following features: presence of more than two metastatic sites (one point); serum albumin <35g/L(one point), lactate dehydrogenase higher than the upper limit of normal (one point). A low score of 0 or 1 suggests a favourable prognosis, whereas a high score of 2 or 3 is associated with an unfavourable outcome.
9. What other options are available to this woman if she progresses?
Patients who remain well can be considered for another clinical study. Palliative care support should be sought at an early stage.
Treatment and follow-up
The patient was treated with a PARP inhibitor for 2 years. This resulted in a maintained partial response and sustained reduction in CA-125 levels.
Further reading
Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. Journal of Clinical Oncology 2008; 26: 3785–3790.
Cancer Research UK. Phases of trials; 2012. Available at: <http://www.cancerresearchuk.org/cancer-help/trials/types-of-trials/phase-1-2-3-and-4-trials>
Eisenhauer EA, O Dwyer PJ, Christian M, Humphrey JS. Phase I clinical trial design in cancer drug development. Journal of Clinical Oncology 2000; 18: 684–692.
Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. New England Journal of Medicine 2009; 361: 123–134.
Olmos D, A’hern RP, Marsoni, S, et al. Patient selection for oncology phase I trials: a multi-institutional study of prognostic factors. Journal of Clinical Oncology 2012; 30: 996–1004.