ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration‐resistant prostate cancer patients: A phase Ib study

Abstract Background ModraDoc006 is an oral formulation of docetaxel, which is co‐administered with the cytochrome P450 3A4 and P‐glycoprotein inhibitor ritonavir (r): ModraDoc006/r. Weekly treatment with ModraDoc006/r had been evaluated in phase I trials in patients with different types of advanced solid tumors, but up to this point in time not in patients with metastatic castration‐resistant prostate cancer (mCRPC). Aim We assessed safety and pharmacokinetics (PK) of ModraDoc006/r to establish the recommended phase 2 dose (RP2D) in patients with mCRPC. Methods mCRPC patients, treatment naïve or following abiraterone or enzalutamide treatment, were included. Dose‐escalation of ModraDoc006/r was based on safety and docetaxel PK. Antitumor activity was assessed by serum prostate‐specific antigen (PSA) and radiological evaluation. Results Cohort 1 (n = 5) received once weekly ModraDoc006 30 mg with ritonavir 100 mg in the morning, and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30‐20/100‐100). The mean docetaxel area under the plasma concentration‐time curve (mAUC0‐inf) was 461 ng/mL × h with 1 dose limiting toxicity (DLT); grade 3 alanine transferase increase. In cohort 2 (n = 6, ModraDoc006/r 30‐20/200‐200), the mAUC0‐inf was 1687 ng/mL × h with 2 DLTs; grade 3 diarrhea and mucositis. In cohort 3A (n = 6, ModraDoc006/r 30‐20/200‐100), the mAUC0‐inf was 1517 ng/mL × h with 1 DLT; grade 3 diarrhea. In cohort 3B (n = 3, ModraDoc006/r 20‐20/200‐100), the mAUC0‐inf was 558 ng/mL × h without DLTs. The mAUC0‐inf exceeded estimated exposures of intravenous docetaxel in cohort 2 and 3A, was lower in cohort 1 and was in range in cohort 3B. PSA decreases of >50% occurred in 6/10 evaluable patients throughout the various cohorts. In five radiological evaluable patients, two confirmed partial responses were observed. Conclusion The RP2D was established at weekly ModraDoc006/r 30‐20/200‐100. Observed PSA and radiological responses suggest promising clinical activity. These results have led to an ongoing randomized Phase 2b study, comparing weekly ModraDoc006/r with 3‐weekly IV docetaxel in patients with mCRPC.

Oral administration of anticancer drugs is often preferred by patients over IV administration. 3 Moreover, docetaxel formulated as an oral drug does not require dexamethasone prophylaxis and can be more costeffective. 4,5 However, oral administration is difficult due to a low bioavailability of docetaxel after oral intake. Oral docetaxel bioavailability is pharmacologically hampered by the drug efflux pump P-glycoprotein (Pgp) and the eliminating enzyme cytochrome P450 (CYP)3A4-both effects have been addressed by co-administration of ritonavir, which inhibits both CYP3A4 and P-gp. [6][7][8] In addition, it is suggested that ritonavir may increase the antitumor activity of docetaxel by inhibition of the CYP3A4-mediated metabolism of the drug within prostate cancer cells. 9 Furthermore, the oral bioavailability of docetaxel is pharmaceutically hampered by its low water solubility, which was solved by production of a solid docetaxel dispersion containing a hydrophilic carrier and surfactant, known in tablet form as ModraDoc006. 10 ModraDoc006 with ritonavir (ModraDoc006/r) treatment has been investigated in patients with different solid tumors, but not specifically in mCRPC patients. 11 A recent meta-analysis revealed that mCRPC patients treated with IV docetaxel have a lower docetaxel exposure compared to patients with other solid tumors. 12 This warrants optimal dose assessment of ModraDoc006/r, in particular in patients with mCRPC. We therefore explored the safety, pharmacokinetics (PK) and recommended phase 2 dose (RP2D) of weekly ModraDoc006/r in patients with mCRPC, as first treatment or following abiraterone or enzalutamide.

| Study design and treatment
The primary aim of this multicenter open label phase Ib study was to establish the RP2D of ModraDoc006/r in a once weekly bi-daily (BID) schedule in mCRPC patients. Dose-escalation and establishment of the RP2D were based on the maximum tolerated dose (MTD) and PK results.
Cohort 1 was dosed at the RP2D of the previous phase 1 study; 30 mg ModraDoc006 plus 100 mg ritonavir in the morning, followed by 20 mg ModraDoc006 plus 100 mg ritonavir in the evening (30-20/100-100). 11 During the first two weekly cycles, patients were admitted to the hospital for supervised administration of ModraDoc006/r (docetaxel as Mod-raDoc006 10 mg tablets and ritonavir as Norvir 100 mg tablets) with 7 hours between the morning and evening dose, while fasting 1 hour before and after the administration. Granisetron premedication was given before every administration during the first two cycles and upon indication in subsequent cycles. Daily prednisolone (BID 5 mg) was started with the study treatment. Patients received no dexamethasone premedication. From cycle 3 onwards, ModraDoc006/r was used at home in a once weekly schedule (with 7-10 hours between the two daily administrations) for a maximum of 30 cycles. Early drug discontinuation was pursued in case of progressive disease (PD), inadequate docetaxel exposure or grade ≥ 3 related adverse events (AEs) despite a maximum of two dose reductions.

| Patient eligibility
Patients with mCRPC considered eligible for standard palliative docetaxel were enrolled. All patients were treatment naïve or had previously received abiraterone or enzalutamide for castration-resistant disease. A World Health Organization Performance Status (WHO PS) of ≤2 and life expectancy of ≥3 months were required. Castration-resistant disease was defined as biochemical and/or radiological progression according to the Prostate Cancer Working Group 3 (PCWG3) recommendations. 13 Hemoglobin levels of ≥10 g/dL, absolute neutrophil counts of ≥1.5 × 10 9 /L, platelet counts of ≥100 × 10 9 /L, serum testosterone levels of ≤50 ng/dL (≤1.73 nmol/L) and adequate hepatic and renal functions were required for inclusion. Patients with bowel obstructions or motility disorders that could hamper the intake or absorption of drugs were excluded. The use of concomitant CYP3A4 or P-gp modulating drugs was not allowed, including bicalutamide <14 days prior to start of ModraDoc006/r. Prior treatment with chemotherapy was not allowed.

| Safety
Weekly safety assessments during the first 10 weeks and every subse- were defined as grade ≥ 3 AEs that were possibly, probably, or definitely related to ModraDoc006/r, occurring in the first 4 weeks of treatment despite optimal supportive care. The following toxicities were considered DLTs: grade ≥ 3 nonhematologic toxicity, grade ≥ 4 anemia and thrombocytopenia or grade 3 thrombocytopenia with bleeding, grade ≥ 3 (febrile) neutropenia or inability to continue study treatment within 7 days of scheduled dosing due to toxicity related to ModraDoc006/r. If ≥2/6 patients experienced a DLT, this dose was considered nontolerable. For the MTD, ≤1 dose limiting toxicity (DLT) in six patients was allowed.
Patients who received ≥1 dose of ModraDoc006/r were evaluable for AEs. Patients who did not complete the first four treatment cycles due nondrug-related events or had clinically relevant drug-drug interactions (DDIs), were considered nonevaluable for DLTs and were replaced. Safety follow-up continued until 28 days after the last intake of ModraDoc006/r.

| Pharmacokinetics
Venous blood samples for PK analysis were obtained at 16 time-points up to 48 hours after intake of the first two cycles of ModraDoc006/r.
Because of the influence of the CYP3A4-inducer enzalutamide on the PK of ModraDoc006/r in patients in cohort 1, sampling in the subsequent cohorts was performed at cycle 1 and cycle ≥5 in patients using enzalutamide ≤28 days prior to the first administration of ModraDoc006/ r. 14 Blood samples were collected in 4 mL lithium heparin tubes, centrifuged at 1500g at 4 C for 10 minutes and stored at −20 C within 1 hour after sampling. Plasma docetaxel and ritonavir concentrations were measured by a validated bioanalytical assay with a lower limit of quantification of docetaxel and ritonavir of 0.5 and 2.0 ng/mL, respectively. 15 Docetaxel and ritonavir PK characteristics were quantified by noncompartmental analyses, using the R software (version 3.6.1). 16 For all cohorts, to ensure adequate PK and in view of potential intra-patient variation, a relatively high pre-specified target (mAUC 0-inf of 800 ng/mL × h) was applied in our study to guide our dose-escalation, based on the reported estimated weekly exposure of 600 ng/mL × h with IV docetaxel in mCRPC patients. 12

| Antitumor activity
Patients that received ≥9 weekly cycles of ModraDoc006/r were considered evaluable for response. This was assessed with prostate-specific antigen (PSA) measurements, computed tomography and bone scintigraphy every 6 weeks. Biochemical response was defined as a PSA decline of ≥50% from baseline (≤2 weeks before start), preferably confirmed by a second PSA value ≥4 weeks later. 13 Radiological response was defined as a complete or partial regression of measurable target lesions (RECIST version 1.1) compared to baseline, confirmed by a second scan ≥6 weeks later. Radiographic progression was assessed per RECIST criteria and bone progression according to the PCWG3 recommendations. 13 3 | RESULTS

| Patient characteristics and study treatment
Baseline characteristics of the patients are summarized in Table 1. Of the 24 enrolled patients, 1 did not start with ModraDoc006/r and 2 were included in the baseline population but not in the PK and safety analysis because of DDIs. All patients had bone metastases, while 43% also had lymph node metastases and 35% had visceral metastases. Thirteen out of 23 (57%) patients had received prior therapy with either enzalutamide or abiraterone. In three out of eight patients with prior enzalutamide, this was discontinued <28 days prior to initiation of ModraDoc006/r. In total, five patients had a DDI with ModraDoc006/r (one with mirabegron, one with methotrexate, three with enzalutamide). At study enrollment, 4 patients had a biochemical PD only, 8 patients had radiographic progression only, while 11 patients had combined PD.
As described in Figure 1

| Safety
All drug-related AEs of CTCAE grade ≥ 2 are summarized in Table 2, including the DLTs. Grade ≥ 2 drug-related toxicities, occurring in >10% of patients, were fatigue, anorexia, diarrhea, nausea, dyspepsia and nail toxicity. Except in the two patients with a DDI due to mirabegron and methotrexate, no febrile neutropenia was observed.
Another patient experienced grade 3 febrile neutropenia and grade 2 mucositis, which was considered nonevaluable toxicity due to a DDI with oral methotrexate. In cohort 3B (n = 3), no DLTs were observed.
Therefore, based on the safety and observation of 1 DLT in six evaluable patients, the MTD was established as 30-20/200-100 (Cohort 3A).

Type of progression
PSA only Soft tissue only Bone only PSA and bone PSA and soft tissue PSA, soft tissue, bone

| Pharmacokinetics
Detailed PK results are included in Table S1 and the individual plasma concentration vs time curves of the patients in the last two cohorts are provided in Figure S1A,B. The docetaxel AUC 0-inf per cohort is depicted in Figure 3.
In cohort 1 (n = 5, ModraDoc006/r 30-20/100-100), in cycle Note: In case of multiple grades of the same AE, the worst grade was reported per patient. DLTs are highlighted in bold. Abbreviations: ALAT, serum alanine aminotransferase; ASAT, serum aspartate aminotransferase; N, number of patients. a All CTCAE grade (Gr) ≥ 2 adverse events (AEs) that were possibly, probably or definitely related to ModraDoc006/r. b Including the nonevaluable patient using mirabegron.

| Antitumor activity
As summarized in Figure 2, PSA responses (≥50% decline) were observed in 6 out of 10 evaluable patients (treated with ≥9 ModraDoc006/r cycles). In five patients with RECIST measurable disease, two confirmed partial responses (both in cohort 3B) were observed.

| DISCUSSION
In this study, we assessed the safety and PK of weekly For each patient, the AUC 0-inf of two treatment cycles of ModraDoc006/r was included. Each dose level is represented by one color, as stated in the legend. Each box represents the median AUC 0-inf with the 25% and 75% percentile and the whiskers indicate the minimum and maximum AUC 0-inf that was observed in the cohort. The pre-specified exposure target is indicated by the dotted line other solid tumors. 12 It is suggested that this can be attributed to effects of medical castration. 17 Despite a higher docetaxel clearance, a similar CYP3A4 activity was observed in castrated vs noncastrated prostate cancer patients. 17 As the expression of drug transporters and hepatic uptake of docetaxel was increased in castrated animal models, it is hypothesized that this results in a higher CYP3A4-mediated clearance. 17 In addition, with oral docetaxel treatment, inhibition of CYP3A4 by ritonavir is required for the systemic uptake. Because ritonavir is a CYP3A4 substrate itself, a higher clearance by CYP3A4 results in lower plasma concentrations of this booster drug, as was indeed observed in this study.
The combination of a higher clearance and lower uptake will lead to a lower docetaxel exposure in mCRPC patients treated with ModraDoc006/r. This problem was successfully addressed by increasing the ritonavir dose in the subsequent cohorts.

ETHICAL STATEMENT
The study was approved by medical ethical board of all participating hospitals. The study was performed in accordance with the Declaration of Helsinki. All patients signed informed consent before the start of any study-related procedures.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.