ModraDoc006/r vs Docetaxel IV in Metastatic Prostate Cancer

This is a multicenter phase 2b study to evaluate the efficacy and tolerability of ModraDoc006 in combination with ritonavir (denoted ModraDoc006/r) in patients with metastatic castration-resistant prostate cancer, suitable for treatment with a taxane.

This is an open label 1:1 randomized Phase 2b trial to determine the efficacy and tolerability of oral ModraDoc006/r versus i.v. docetaxel in mCRPC subjects. Cohort 1 will receive i.v. docetaxel at 75 mg/m2 every 3 weeks (Q3W). Cohort 2 will receive 30 mg ModraDoc006 in combination with 200 mg ritonavir in the morning and 20 mg ModraDoc006 in combination with 100 mg ritonavir in the evening (7-12 hours after the morning dose), on Day 1, 8 and 15 of a 21-day cycle (BIDW). All patients will also receive 5 mg oral prednisone twice daily. Treatment in both cohorts will continue until disease progression, unacceptable toxicity, or discontinuation for any other reason. The end of the trial is defined as the time point when all subjects have discontinued trial treatment and have been given follow-up for safety measurements according to the trial assessment schedule.

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥ 18 years
2. Histologically or cytologically proven prostate cancer with evidence of progressive mCRPC, defined as:

   1. Castrate levels of testosterone, defined as ≤ 50 ng/dL (or ≤ 0.50 ng/mL or 1.73 nmol/L)
   2. Evidence of progressive metastatic disease as defined by radiographic disease progression or Prostate Specific Antigen (PSA) progression
   3. With an indication for systemic treatment with docetaxel according to the standard of care
3. Measurable tumour lesions, defined as pelvic and/or extra-pelvic nodal lesions ≥1.5 cm in the short axis or visceral lesions ≥1.0 cm in the longest dimensions and measurable according to RECIST v1.1, bone metastasis as evaluated with 99mTc-methylene diphosphonate (MDP) radionuclide bone scintigraphy
4. Resolution of toxicity of prior therapy to \< grade 2 (except for alopecia), as defined by CTCAE v5.0
5. Adequate haematological, renal and hepatic functions:

   1. Hemoglobin ≥ 6.0 mmol/l (\>9.6 g/dL)
   2. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109 /L
   3. Platelet count ≥ 100 x 109 /L
   4. Hepatic function defined by serum bilirubin ≤ Upper Limit of Normal (ULN), Alanine Amino Transferase (ALAT) and Aspartate Amino Transferase (ASAT) ≤ 1.5 x ULN concomitant with alkaline phosphatase ≤ 2.5 × ULN.
   5. Renal function defined by serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 ml/min (by Cockcroft-Gault formula, or MDRD).
6. World Health Organisation Performance Status (WHO-PS) of 0-2
7. Estimated life expectancy of at least 12 weeks
8. Able and willing to swallow oral medication
9. Able and willing to undergo radiologic scans (CT scan)
10. Able and willing to give written informed consent according to local guidelines

Exclusion Criteria:

1. Any treatment with investigational drugs, chemotherapy or immunotherapy within 4 weeks prior to receiving the first dose of investigational treatment. Palliative radiotherapy (1x8 Gy dose) is allowed before and during the study, but not in the week prior to start of study treatment.
2. Subjects who have had prior treatment with taxanes.
3. Subjects with symptomatic brain metastases. Subjects asymptomatic in the absence of corticosteroids and anticonvulsant therapy for ≥6 weeks are eligible. Radiotherapy for brain metastasis must have been completed ≥6 weeks prior to start of trial. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT completed at screening, demonstrating no current evidence of progressive brain metastases). Subjects are not permitted to receive anti-epileptic drugs or corticosteroid treatment indicated for brain metastasis. Subjects with a history of leptomeningeal metastases are not eligible.
4. Current malignancies other than mCRPC with exception of adequately treated basal or squamous cell carcinoma of the skin, or adequately treated non-muscular invasive bladder cancer.
5. Absence of highly effective method of contraception as of cycle one day one (C1D1). Men enrolled in this trial must agree to use a highly effective contraceptive method throughout the study.
6. Uncontrolled hypertension (systolic \> 150 mm Hg and/or diastolic \> 100 mm Hg)
7. Unresolved (\>grade 0 as defined by CTCAE version 5.0) gastrointestinal toxicities (pre-existing mucositis, diarrhea or nausea/vomiting)
8. Grade ≥ 2 motor ≥ 2 motor or sensory neuropathy symptoms (as defined by CTCAE version 5.0)
9. Known hypersensitivity to any of the study drugs or excipients or taxanes
10. Concomitant use of P-glycoprotein (P-gp , MDR), Cytochrome P450 (CYP)3A, Organic Anion-Transporting Polypeptide (OATP)1B1, OATP1B3 and Multidrug resistance-associated protein 2 (MRP2) modulating drugs such as Ca+- entry blockers (verapamil, dihydropyridines), cyclosporine, quinidine and grapefruit juice, concomitant use of HIV medications, other protease inhibitors, (non) nucleoside analogues, or St. John's wort
11. Bowel obstruction or motility disorder that may influence the resorption of drugs as judged by the treating physician
12. Major surgical procedures within 21 days prior to providing informed consent
13. Active acute or chronic infection, which is not controlled by appropriate medication (at the discretion of the treating physician)
14. Known positivity for Human Immunodeficiency Virus HIV-1 or HIV-2 type
15. Patients with known active infection of hepatitis B/C (HBC), or E (patients who are anti-HBC positive but HBsAg negative are eligible to participate in this study)
16. Clinically significant (i.e. active) cardiovascular disease defined as stroke, transient ischemic attack (TIA), myocardial infarction, unstable angina, or congestive heart failure within ≤ 6 months prior to first trial treatment
17. Evidence of any other medical conditions (such as treatment-resistant peptic ulcer disease, erosive oesophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, or pulmonary embolism within 4 weeks of randomization, or psychiatric illness, drug or alcohol abuse, physical examination or laboratory findings) that may interfere with the planned treatment, affect subject compliance or place the subject at high risk of treatment-related complications
18. Legal incapacity