ModraDoc006/r vs Docetaxel IV in Metastatic Prostate Cancer

Study Overview
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Brief Summary
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This is a multicenter phase IIb 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.

Detailed Description
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This is an open label 1:1 randomized Phase IIb 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 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. 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.

Official Title
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A Multicentre Phase IIb Trial to Evaluate the Efficacy and Tolerability of ModraDoc006/r in Subjects With Metastatic Castration Resistant Prostate Cancer (mCRPC), Suitable for Treatment With a Taxane

Conditions
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Prostate Cancer Metastatic, Castration-resistant Prostate Cancer

Intervention / Treatment
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* Drug: Docetaxel in Parenteral Dosage Form
* Drug: ModraDoc006/r


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Histologically or cytologically proven prostate cancer with evidence of progressive mCRPC, defined as: Castrate levels of testosterone, defined as ≤ 50 ng/dL (or ≤ 0.50 ng/mL or 1.73 nmol/L) Evidence of progressive metastatic disease as defined by radiographic disease progression or PSA progression With an indication for systemic treatment with docetaxel according to the standard of care 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 Resolution of toxicity of prior therapy to < grade 2 (except for alopecia), as defined by CTCAE v5.0 Adequate haematological, renal and hepatic functions: Hemoglobin ≥ 6.0 mmol/l (>9.6 g/dL) ANC ≥ 1.5 x 109 /L Platelet count ≥ 100 x 109 /L Hepatic function defined by serum bilirubin ≤ ULN, ALAT and ASAT ≤ 1.5 x ULN concomitant with alkaline phosphatase ≤ 2.5 × ULN. Renal function defined by serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 ml/min (by Cockcroft-Gault formula, or MDRD). WHO performance status of 0-2 Estimated life expectancy of at least 12 weeks Able and willing to swallow oral medication Able and willing to undergo radiologic scans (CT scan) Able and willing to give written informed consent according to local guidelines Exclusion Criteria: 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. Subjects who have had prior treatment with taxanes. 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. 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. 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. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) Unresolved (>grade 0 as defined by CTCAE version 5.0) gastrointestinal toxicities (pre-existing mucositis, diarrhea or nausea/vomiting) Grade ≥ 2 motor ≥ 2 motor or sensory neuropathy symptoms (as defined by CTCAE version 5.0) Known hypersensitivity to any of the study drugs or excipients or taxanes Concomitant use of P-glycoprotein (P-gp , MDR), CYP3A, OATP1B1, OATP1B3 and 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 Bowel obstruction or motility disorder that may influence the resorption of drugs as judged by the treating physician Major surgical procedures within 21 days prior to providing informed consent Active acute or chronic infection, which is not controlled by appropriate medication (at the discretion of the treating physician) Known positivity for Human Immunodeficiency Virus HIV-1 or HIV-2 type Patients with known active infection of hepatitis B, C, or E (patients who are anti-HBC positive but HBsAg negative are eligible to participate in this study) 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 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 Legal incapacity

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: One-hundred RECIST 1.1 evaluable patients will be randomized 1:1 to treatment with ModraDoc006/r versus standard i.v. docetaxel. The treatment outcome will be estimated and used as the basis for the design of the future pivotal phase 3 trial. The sample size of 50 evaluable patients per cohort will provide a sufficiently precise point estimate of the primary endpoint ORR in both groups to calculate the sample size for the pivotal study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Docetaxel IV<br>This study arm will receive docetaxel at 75 mg/m2 given i.v. as a one-hour infusion on day 1 every 21 days plus 5 mg oral prednisone twice daily. | Drug: Docetaxel in Parenteral Dosage Form<br>* Treatment with IV docetaxel at 75 mg/m2 given as a one-hour infusion on day 1 every 21 days plus 5 mg oral prednisone twice daily<br>* Other names: Taxotere;|
| Experimental: ModraDoc006/r<br>This cohort will receive ModraDoc006/r 30 mg oral docetaxel in combination with 200 mg ritonavir in the morning and 20 mg oral docetaxel 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, plus 5 mg oral prednisone twice daily. | Drug: ModraDoc006/r<br>* Treatment with twice daily once weekly (BIDW) ModraDoc006 (oral docetaxel) 10mg tablets in combination with ritonavir 100mg tablets<br>* Other names: oral docetaxel formulation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Evaluation of objective response rate that will be observed as measured by RECIST v1.1 criteria, in patients with metastatic prostate cancer after treatment with ModraDoc006/r or docetaxel IV | From baseline through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse event profile (Safety) | The hematological and non-hematological safety profile of ModraDoc006/r will be assessed by clinical and laboratory evaluations according to CTCAE v5.0. | Evaluation of all adverse events during the complete study treatment until 28 days after the last intake, using the CTCAE v5.0 grading system | 
| PSA Response Rate | PSA decline of >30% and >50% decline from baseline with confirmatory read ≥4 weeks later without clinical / imaging progressive disease (PD) based on the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) recommendations | From baseline through study completion, an average of 1 year | 
| PFS at 6 months | Progression free survival (PFS) at 6 months based on RECIST v1.1 | Landmark analysis after last patient progressed or survived for 6 months after randomization | 
| PSA-PFS | PSA-PFS according to PCWG3 criteria | From baseline through study completion, an average of 1 year | 
| Time to PSA progression | Time from randomization to the time when the PSA increases by 50% above the nadir | From baseline through study completion, an average of 1 year | 
| Time to first skeletal event | Time to first skeletal event, defined as the time from randomisation to the occurrence of the first skeletal-related event (i.e. radiation therapy or surgery to bone, clinically apparent pathological bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain). | From baseline through study completion, an average of 1 year | 
| Duration of response (DOR) | Duration of response (DOR) based on RECIST v1.1 | From baseline through study completion, an average of 1 year | 
| Time to progression (TTP) | Time to progression (TTP) based on RECIST v1.1, incorporating the bone metastatic variable according to PCWG3 | From baseline through study completion, an average of 1 year | 
| Disease control rate (DCR) | Disease control rate DCR) based on RECIST v1.1 | From baseline through study completion, an average of 1 year |