FormalPara Key Points

Despite recent advances in therapy, ovarian cancer mortality remains high, suggesting additional strategies are needed.

Our analysis demonstrates the feasibility of combining rucaparib (500 mg twice daily) and bevacizumab (15 mg/kg every 21 days) as treatment for patients with newly diagnosed, advanced ovarian cancer.

The safety profile of the combination was similar to that reported previously for rucaparib and bevacizumab as single agents.

1 Background

Mortality in patients with ovarian cancer remains high, with only a modest increase in overall survival despite improvements in treatment. Initial response rates to chemotherapy are approximately 80% [1], but the majority of patients who achieve a complete response will relapse within 4–12 months [2, 3].

Targeted agents, such as the antiangiogenic drugs bevacizumab and cediranib, and the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib, niraparib, and rucaparib, have been used to improve patient outcomes, either as single agents or in combination with chemotherapy in patients with newly diagnosed and recurrent disease in the treatment setting or as switch maintenance [4,5,6,7,8,9].

Bevacizumab is a monoclonal antibody that targets the proangiogenic vascular endothelial growth factor. Trials have demonstrated that the addition of bevacizumab to chemotherapy as first-line treatment and as treatment or maintenance for patients with recurrent ovarian cancer can improve progression-free survival (PFS) relative to chemotherapy alone [8, 9]. This may be due to additional antitumor activity on the tumor vasculature, interstitial pressure, and permeability of blood vessels, which allows enhanced delivery of chemotherapy to tumor cells [10].

PARP inhibitors block the enzymatic activity required to form poly(ADP-ribose) chains, which are crucial for the repair of single-strand breaks in DNA. They also trap PARP enzymes at sites of DNA damage, preventing repair. Olaparib, niraparib, and rucaparib all strongly inhibit the enzymatic activity of PARP1 (IC50, 1.9–0.6 nM) and PARP2 (IC50, 0.2–0.5 nM) [11], and have similar potency for DNA trapping [12, 13]. Notably, the PARP inhibitor talazoparib, which is approved for the treatment of patients with breast cancer, has stronger enzymatic inhibition (IC50, 0.5 and 0.1 nM, respectively) and more potent DNA trapping abilities.

BRCA1 and BRCA2 (BRCA1/2)-mutant cell lines and cells deficient in or depleted of homologous recombination proteins (i.e., having homologous recombination repair deficiency [HRD]) other than BRCA1/2 have sensitivity toward PARP inhibitors [14, 15]. Clinical data confirm preclinical evidence, and PARP inhibitors have been approved in “all comers” with platinum-sensitive recurrent ovarian cancer [16,17,18].

Rucaparib is an orally available, small-molecule PARP inhibitor approved for the treatment of patients with recurrent ovarian cancer either as a single agent or as maintenance treatment in those responding to platinum-based chemotherapy [6, 19]. The recommended starting dose of rucaparib is 600 mg twice daily (BID). In clinical trials, rucaparib was found to be generally well tolerated, with treatment-emergent adverse events (TEAEs) common to the PARP inhibitor class (e.g., fatigue, gastrointestinal events, hematologic events) that could be managed with supportive care or dose modifications [6, 20]. Notably, some TEAEs are more common with certain PARP inhibitors than others, such as a higher incidence of thrombocytopenia and hypertension with niraparib vs olaparib or rucaparib, and a higher incidence of increased alanine/aspartate aminotransferase levels with rucaparib vs olaparib or niraparib [21, 22].

The combination of an antiangiogenic agent and a PARP inhibitor is being studied in a number of clinical trials given the reported synergistic effect of the drugs. Inhibiting angiogenesis leads to hypoxia, which has been shown to induce HRD through the downregulation of homologous recombination repair genes, which may result in increased sensitivity of tumor cells to PARP inhibitors [23,24,25]. The combination of a PARP inhibitor (olaparib capsules 200 mg BID) and an angiogenesis inhibitor (cediranib 30 mg BID) improved PFS by approximately 8 months compared with PARP inhibition alone (olaparib capsules 400 mg BID; hazard ratio = 0.42) in a phase II study of women with platinum-sensitive, relapsed, high-grade ovarian cancer [26]. The combination of niraparib (300 mg daily) and bevacizumab (15 mg/kg day 1 every 21 days [d1 q21d]) significantly improved PFS compared with niraparib 300 mg daily alone (adjusted hazard ratio = 0.35) in patients with recurrent, platinum-sensitive ovarian cancer [27]. Maintenance treatment with olaparib tablets (300 mg BID) combined with bevacizumab (15 mg/kg q21d) improved PFS compared with bevacizumab maintenance alone (hazard ratio = 0.59) in patients with advanced ovarian cancer who had responded to first-line platinum-taxane chemotherapy plus bevacizumab [28]. Across studies, adverse events (AEs) with the combinations were consistent with the known safety profiles of the single agents, although some AEs were more frequent in the combination arms vs the single-agent arms.

Here, we present data from the phase I portion of the MITO 25 study evaluating maintenance treatment with rucaparib with or without bevacizumab in patients with newly diagnosed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. As no data exist for rucaparib when administered concomitantly with bevacizumab, this pharmacokinetic (PK) and dose-escalation portion was designed to determine the maximum tolerated dose (MTD) of rucaparib in this combination, provide early indications of the safety of the combination, and establish the PK profile of rucaparib when administered with bevacizumab. The efficacy of rucaparib maintenance treatment with or without bevacizumab will be further evaluated in the randomized phase II portion of MITO 25.

2 Methods

This is a single-arm, phase I dose-escalation study performed in a single institution. The trial was approved by the Fondazione IRCCS National Cancer Institute of Milan Ethical Committee and registered with ClinicalTrials.gov (NCT03462212).

2.1 Patients and Study Design

Patients provided written informed consent before participating in the study. Patients with newly diagnosed, histologically confirmed, high-grade serous, endometrioid, and clear-cell International Federation of Gynecology and Obstetrics staging system (FIGO) stage IIIB to IV epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer were enrolled. Patients had to have an Eastern Cooperative Oncology Group Performance Status of 0 or 1, and adequate renal, hepatic, and bone marrow function. Patients who received prior anticancer treatment were excluded.

Cohorts of three patients at a time were recruited using the Fibonacci triplets design to assess the effects of increasing doses of rucaparib (400 mg, 500 mg, and 600 mg BID) as a continuous oral administration in combination with bevacizumab at the fixed intravenous dose of 15 mg/kg administered on d1 q21d.

Three patients were recruited into the first cohort (rucaparib 400 mg BID). If no serious side effect (SSE) representing a dose-limiting toxicity (DLT; see criteria below) was reported in the first three patients, the second cohort was treated at the next dose level. If one SSE was reported in the first cohort, three more patients were to be enrolled at the same dose. If no SSEs were reported in these three patients, the second cohort was to be opened and treated as above. If one or more SSEs was reported in the further three enrolled patients, the MTD was identified as the previous rucaparib concentration.

2.2 Objectives

The primary objective was to identify the MTD of the rucaparib-bevacizumab combination in patients with stage IIIB to IV ovarian cancer. Secondary objectives were to evaluate the hematologic and nonhematologic toxicity of the rucaparib-bevacizumab combination and evaluate the PK of rucaparib when co-administered with bevacizumab in patients receiving this combination.

2.3 Dosing Schedule and Dose Escalation

All patients were treated with carboplatin area under the concentration–time curve (AUC) 5 in combination with paclitaxel 175 mg/m2 d1 q21d and bevacizumab 15 mg/kg d1 q21d for six cycles. In the case of interval debulking surgery, bevacizumab was held for ≥ 28 days before and after the surgery; held doses of bevacizumab could be replaced to complete the maximum number of cycles. At chemotherapy completion, non-progressing patients continued to receive intravenous bevacizumab q21d as maintenance for a maximum of 22 total cycles, including the cycles in combination with chemotherapy. Combination with oral rucaparib as maintenance was started within 9 weeks of chemotherapy completion. The first dose of oral rucaparib was given 7 days prior to bevacizumab administration to allow the opportunity to observe any acute drug reactions and to collect rucaparib PK data prior to bevacizumab administration. Oral rucaparib (400 mg, 500 mg, or 600 mg BID depending on cohort) was administered in 28-day cycles. Similar to prior studies [6, 20], patients received rucaparib until disease progression or unacceptable toxicity.

DLTs were assessed in patients receiving the rucaparib-bevacizumab combination. DLTs were defined as follows:

  • More than ten missed doses in the preceding 28 days due to study drug-related toxicity;

  • A delay of more than 14 days in initiating cycle 2 due to study drug-related toxicity;

  • Discontinuation of the patient due to study drug-related toxicity before completing cycle 1;

  • A nonhematologic event, including grade ≥ 3 nausea, vomiting, or diarrhea lasting more than 3 days despite optimal supportive medications; or any other grade ≥ 3 nonhematologic toxicity with the exception of transient (< 7 days), grade 3 transaminase elevation;

  • A hematologic event, including grade 4 neutropenia (absolute neutrophil count < 500/mm3) lasting ≥ 7 days; febrile neutropenia (absolute neutrophil count < 500/mm3 with a fever ≥ 38.5°C); or grade ≥ 3 thrombocytopenia (platelet count < 50,000/mm3) persisting for ≥ 5 days or grade ≥ 3 thrombocytopenia associated with bleeding.

The MTD was defined as the dose level below which no more than one out of three patients or a total of two out of six patients had DLTs. A DLT was defined as the occurrence of one of the above events during the first two cycles of drug administration, which was considered at least possibly related to the study drugs. To further safeguard the well-being of the patients, two patients in each cohort were enrolled in parallel and observed for two cycles of treatment; if no DLT occurred, a third patient was enrolled.

After the MTD was determined, the patients continued treatment until disease progression, unacceptable toxicity, or refusal of further treatment. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03.

2.4 Pharmacokinetic Sampling and Analysis

Blood samples for the rucaparib PK analysis were drawn from each patient during cycle 1 on day −7 (acute administration), day 1 (bevacizumab infusion), and day 21 and at 1, 2, 3, 4, 6, 8, and 24 hours post-dose. Plasma concentrations were determined using a validated high-performance liquid chromatography method combined with mass spectrometry, which was performed with a minor modification from the method used by Sparidans et al. [29].

Pharmacokinetic parameters were calculated from the concentration–time data using a noncompartmental analysis. Rucaparib parameters obtained on days 1 and 21 were compared with those obtained on day −7 to compare the steady-state condition of rucaparib after bevacizumab infusion with that of rucaparib prior to bevacizumab coadministration. The rucaparib PK parameters were also compared to what was reported in the investigator brochure of the drug referring to historical controls.

The following parameters were obtained for rucaparib: maximum plasma concentration (Cmax) at steady state, minimal plasma concentration at steady state, and AUC at steady state. Cmax, time to Cmax (Tmax), and AUC from 0 to 8 hours were determined at the first administration on day − 7.

2.5 Statistical Analysis

Descriptive statistics were calculated for the PK parameters: mean, standard deviation, coefficient of variation, median, and geometric mean using SAS, Version 9.3.

3 Results

We enrolled nine patients, three in each dose cohort, from April 2018 to March 2019. Patient baseline demographics and disease characteristics for each dose subgroup are reported in Table 1.

Table 1 Patient baseline demographics and disease characteristics
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3.1 Safety

The AEs experienced by patients in each dose group are summarized in Table 2. Patients in all groups had arthralgia and nausea, whereas hypertension, dysgeusia, and diarrhea became more common in the higher dosage groups. The majority of AEs were grade 1 or 2, and were thought to be related to rucaparib or bevacizumab.

Table 2 Adverse eventsa
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Two patients in the 600-mg group had four grade 3 TEAEs: one patient had grade 3 increased alanine aminotransferase and aspartate aminotransferase levels lasting 10 days and another patient had grade 3 depression and hallucinations.

3.2 Maximum Tolerated Dose

No DLTs occurred in the rucaparib 400- or 500-mg dose groups. The alanine aminotransferase elevation and the depression and hallucination events were considered DLTs related to rucaparib. Alanine aminotransferase elevations have been reported in trials of patients receiving rucaparib for recurrent disease, and depression has been reported with other PARP inhibitors. Although hallucinations were never reported, given the complete resolution of the symptoms after rucaparib discontinuation, we concluded that were rucaparib related. Because both of these SSEs occurred in the 600-mg group and affected two out of three patients, the MTD for rucaparib in combination with bevacizumab 15 mg/kg d1 q21d was identified to be 500 mg BID (i.e., the dose level below the group in which the DLTs occurred).

3.3 Pharmacokinetics

Table 3 summarizes the mean PK data over time for rucaparib at the three dose levels, administered alone and in combination with bevacizumab. Despite the clear limitations represented by the small sample size, the narrow dose range, and the high PK variability, plasma exposure of rucaparib was approximately dose proportional. The values of Tmax ranged from 1.7 to 5 hours, suggesting a relatively fast absorption. The range of trough concentrations (i.e., the lowest concentration before the next dose was administered) was 1.5–1.6, 1.8–2.0, and 1.6–2.1 μg/mL at doses of 400, 500, and 600 mg BID, respectively. Rucaparib reached steady-state levels on days 1 and 21, with the Cmax and AUC being two to three times higher than those determined on day −7.

Table 3 Pharmacokinetic (PK) data for rucaparib with and without bevacizumab co-administration
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Figure 1 shows the mean concentration–time profiles of patients treated with the three doses, and Fig. 2 compares the concentration–time profiles for the three groups at the three timepoints. No substantial difference in PK parameters was found between the three-dose cohorts or in the PK profiles of rucaparib when administered prior to or concomitantly with bevacizumab with respect to historical controls as reported in the rucaparib prescribing information.

Fig. 1
figure 1

Concentration–time profiles of patients treated with rucaparib (a) 400 mg, (b) 500 mg, and (c) 600 mg twice daily. Colored dots represent the rucaparib concentration measured for each individual; the data in black represent the mean rucaparib concentration. Pt patient

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Fig. 2
figure 2

Comparison of mean concentration–time profiles of patients treated with rucaparib 400 mg, 500 mg, and 600 mg twice daily. Error bars represent standard deviation

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4 Discussion

This phase I dose-escalation study evaluated the use of rucaparib and bevacizumab as maintenance treatment in patients with newly diagnosed, FIGO stage IIIB–IV ovarian, primary peritoneal, or fallopian tube cancer who had responded to carboplatin/paclitaxel chemotherapy plus bevacizumab. The MTD of rucaparib was 500 mg BID when co-administered with bevacizumab 15 mg/kg d1 q21d. There were no new safety concerns arising from the use of the combination of rucaparib and bevacizumab in these patients. The plasma–concentration time profiles of rucaparib administered with bevacizumab were similar to those of rucaparib as a single agent reported historically. The randomized phase II portion of MITO 25 will expand evaluation of maintenance treatment with rucaparib in combination with bevacizumab in patients with chemotherapy-naïve, advanced ovarian cancer.

The phase I portion of MITO 25 utilized a standard Fibonacci triplets design to evaluate the combination. Two patients in the rucaparib 600-mg group had DLTs, including a grade 3 transaminases elevation lasting more than 7 days and a grade 3 neurological event. Per protocol, the next lower dose (500 mg BID) was declared the MTD when taken in combination with the bevacizumab dose of 15 mg/kg d1 q21d. A grade 3 alanine aminotransferase/aspartate aminotransferase increase is a known side effect of rucaparib and can be managed according to the summary of product characteristics [19].

Depression has been reported with other PARP inhibitors but not with rucaparib, nor were hallucinations. Nevertheless, the two symptoms were considered treatment related as the patient had no prior history of depression or hallucinations and rucaparib was the only new treatment added to the long-lasting therapy of the patient. Furthermore, these symptoms completely disappeared after rucaparib discontinuation.

The overall safety profile was similar to that reported in previous studies of single-agent rucaparib and single-agent bevacizumab [6, 8, 9, 20, 30, 31]. The most frequent bevacizumab-related AE was hypertension as reported in the registration trial [8]. In the phase III ARIEL3 study, patients were treated with rucaparib 600 mg BID as a single agent [6]. The most common TEAEs were nausea, asthenia or fatigue, dysgeusia, anemia or decrease hemoglobin, constipation, and vomiting. Grade 3 or higher TEAEs were reported in 56% of patients taking rucaparib, the most common of which were anemia (19%), and increased alanine aminotransferase or aspartate aminotransferase levels (11%). In ARIEL3, a dose reduction due to a TEAE occurred in 55% of patients in the rucaparib group; therefore, it is not surprising that a lower dosage would be recommended when rucaparib is taken in combination with another agent [6]. A similar safety profile was also reported for patients in the phase II ARIEL2 study [31]. TEAEs  observed in our phase I portion of MITO 25 were also generally similar to those reported in other studies evaluating PARP inhibitors in combination with bevacizumab [27, 28]. Across those studies, the most common any-grade TEAEs in the combination arms were nausea, fatigue, hypertension, and anemia. The combination arms generally had higher incidence of grade 3 or greater TEAEs, with the most common being hypertension and anemia.

At the three dose levels investigated, rucaparib exhibited dose-related plasma concentration–time profiles in line with those observed after repeated administration of the agent given on its own, with the accumulation of the drug two to three times that of the concentration obtained after acute administration (day −7). In the patients studied, there were no substantial differences in the PK profiles of rucaparib when it was administered alone or concomitantly with bevacizumab. In addition, the PK parameters were consistent with those reported in earlier studies on the PK of rucaparib administered as a single agent [30, 32].

The combination of bevacizumab 15 mg/kg d1 q21d plus rucaparib 500 mg BID will be used in the multicenter phase II portion of MITO 25 in patients with newly diagnosed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients with HRD-negative tumors will be randomized (1:1:1) to one of three arms: carboplatin-paclitaxel chemotherapy plus bevacizumab followed by bevacizumab-only maintenance treatment (Arm A), carboplatin-paclitaxel chemotherapy followed by rucaparib-only maintenance treatment (Arm B), or carboplatin-paclitaxel chemotherapy plus bevacizumab followed by bevacizumab plus rucaparib maintenance treatment (Arm C). Patients with HRD-positive tumors will be randomized (1:1) to either Arm B or Arm C. The primary endpoint of phase II is PFS, and secondary endpoints include overall survival, response rate, time to subsequent therapy, safety and tolerability, and quality of life. The investigators will enroll 290 patients; recruiting will begin in the third quarter of 2020 and the trial is expected to run for approximately 5 years.