Hoping for a New Horizon : Phase I oncology clinical trials medical outcomes & patients’ perspectives

The primary aim of phase I trials is to establish safety profiles. Patients with advanced cancer, without standard treatment options, may struggle to decide whether to engage in a treatment with unknown efficacy, benefit, and side effects, or to opt for symptom-oriented palliative care. In this thesis, both medical outcomes of phase I clinical trials, as well as research towards patients‘ perspectives are presented

A phase 1 study of PARP-inhibitor ABT-767 in advanced solid tumors with BRCA1/2 mutations and high-grade serous ovarian, fallopian tube, or primary peritoneal cancer

Purpose This phase 1 study examined safety, pharmacokinetics (PK), and efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-767 in patients with advanced solid tumors and BRCA1/2 mutations or with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Methods Patients received ABT-767 monotherapy orally until disease progression or unacceptable toxicity. Dose was escalated from 20 mg once daily to 500 mg twice daily (BID). Dose-limiting toxicities, recommended phase 2 dose (RP2D), food effect, objective response rate, and biomarkers predicting response were determined. Results Ninety-three patients were treated with ABT-767; 80 had a primary diagnosis of ovarian cancer. ABT-767 demonstrated dose-proportional PK up to 500 mg BID and half-life of ~2 h. Food had no effect on ABT-767 bioavailability. Most common grade 3/4 treatment-related adverse events were nausea, fatigue, decreased appetite, and anemia. Anemia showed dose-dependent increase. RP2D was 400 mg BID. Objective response rate by RECIST 1.1 was 21% (17/80) in all evaluable patients and 20% (14/71) in evaluable patients with ovarian cancer. Response rate by RECIST 1.1 and/or CA-125 was 30% (24/80) in patients with ovarian cancer. Mutations in BRCA1 or BRCA2, homologous recombination deficiency (HRD), and platinum sensitivity were associated with tumor response. Median progression-free survival was longer for HRD positive (6.7 months) versus HRD negative patients (1.8 months) with ovarian cancer. Conclusions ABT-767 had an acceptable safety profile up to the established RP2D of 400 mg BID and dose-proportional PK. Patients with BRCA1 or BRCA2 mutation, HRD positivity, and platinum sensitivity were more sensitive to ABT-767

“If only I had”, patients’ experiences during early oncology trials

Purpose: Until today, it is not clear why patients decide to continue with early clinical trial (ECT) participation. Therefore, the aim of this study is to explore to which extent the self-determination theory of Ryan and Deci, according to the ECT enrollment phase, corresponds to the motivations of participants during ECT’s. Methods: This study has a qualitative design. Data were collected using semistructured interviews and were deductively analyzed in Nvivo12 using the thematic analysis approach of Braun and Clarke. Results: As a result of the deductive analysis performed, six themes and twenty subthemes emerged which matched the three personal needs: competence, relatedness, and autonomy (n = 11). “Competence” included the following themes: mixed future expectations, treatment expectations, and control of the outcome. “Relatedness” included the theme altruistic motivation. “Autonomy” included the themes; to live and act in harmony as well as mental and physical burden. Conclusion: Participants felt they tried everything and that they were treated to the limit. This not only gives the motivation to continue participating but also a sense of altruism. Despite different burdens, side-effects, and the feeling of being a test subject, the participants will not easily choose to stop participation in order to prevent saying afterwards: “If only I had”

A phase 1 study of PARP-inhibitor ABT-767 in advanced solid tumors with BRCA1/2 mutations and high-grade serous ovarian, fallopian tube, or primary peritoneal cancer

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Evaluation of patient enrollment in oncology phase I clinical trials

Introduction. For anticancer drug development, it is crucial that patients participate in early-phase clinical trials. The main aim of this study was to gain insight into the motivations and other variables influencing patients in their decision to participate in phase I oncology trials. Materials and Methods. Over a period of 25 months, all patients who were informed about (specific) phase I trials in our cancer center were retrospectively included in this study. Data on providing informed consent and final phase I enrollment were collected. Results. In total, 365 patients, with a median age of 59 years and a median World Health Organization performance status score of 1, were evaluated. The majority of patients (71%) were pretreated with systemic therapy, with a median of two lines. After specific study information had been given, 145 patients (40%) declined informed consent, 54% of them mainly because of low expectations regarding treatment benefits and concerns about potential side effects. Patients who had received previous systemic therapy consented more frequently than others. After initial consent, 61 patients (17%) still did not receive study treatment, mostly because of secondary withdrawal of consent or rapid clinical deterioration prior to first dosing. Discussion. After specific referral to our hospital for participation in early clinical trials, only 44% of all patients who were informed about a specific phase I trial eventually participated. Reasons for both participation and nonparticipation were diverse. Patient participation rates could be improved by forming an experienced and dedicated study team