| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic Castration Resistant Prostate Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the efficacy of ModraDoc006/r, as measured by radiographic Progression Free Survival (rPFS), compared to standard treatment with i.v. docetaxel in subjects with mCRPC. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of ModraDoc006/r, as measured by PCWG3-modified RECIST v1.1 criteria of objective response rate (ORR), disease control rate (DCR) and duration of response (DOR) compared to standard treatment with i.v. docetaxel in subjects with mCRPC.
• To evaluate the clinical outcome in terms of rPFS at 6 months and time to progression (TTP) of ModraDoc006/r compared to i.v. docetaxel
• To evaluate the outcome in terms of PSA tumor marker evaluation for PSA response, PSA-PFS and time to PSA progression of ModraDoc006/r compared to i.v. docetaxel
• To compare the time to first skeletal-related event between ModraDoc006/r and i.v. docetaxel
• To determine the safety and tolerability of ModraDoc006/r compared to i.v. docetaxel
• To compare subject's Health Related Quality of Life (HRQoL) response of ModraDoc006/r and docetaxel i.v. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18 years
2. Histologically or cytologically proven prostate cancer with evidence of progressive mCRPC, defined as:
a. Castrate levels of testosterone, defined as ≤ 50 ng/dL (or ≤ 0.50 ng/mL or 1.73 nmol/L)
b. Evidence of progressive metastatic disease as defined by radiographic disease progression or PSA progression
c. With an indication for systemic treatment with docetaxel according to the standard of care
3. Evaluable disease, defined as nodal or visceral lesions as evaluated with CT-scan or MRI, and measured according to RECIST v1.1. and/or bone metastasis as evaluated with 99mTcmethylene diphosphonate (MDP) radionuclide bone scintigraphy by PCWG3 criteria
4. Resolution of toxicity of prior therapy to < grade 2 (except for alopecia), as defined by CTCAE v5.0. For any pre-existing gastro-intestinal toxicities (diarrhea or nausea/vomiting) and mucositis, full resolution is required prior to study start.
5. Adequate hematological, renal and hepatic functions:
a. Hemoglobin ³ 5.6 mmol/l (>9.0 g/dL)
b. ANC ≥ 1.5 x 109 /L
c. Platelet count ≥ 100 x 109 /L
d. Hepatic function defined by total bilirubin ≤ 1.5 x ULN, except for patients with familial bilirubinemia (Gilbert's disease) and Serum ASAT and ALAT ≤ 2.5 x ULN (≤ 5 x ULN with liver metastases)
e. Renal function defined by serum creatinine ≤ 1.5 x ULN or creatinine clearance 50 ml/min (by Cockcroft-Gault formula, or MDRD [Modification of Diet in Renal Disease]).
6. WHO performance status 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, or MRI and bone scintigraphy)
10. Able and willing to give written informed consent according to local guidelines |
|
| E.4 | Principal 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. Grade ≥ 2 motor or sensory neuropathy symptoms (as defined by CTCAE version 5.0)
8. Known hypersensitivity to any of the study drugs or excipients or taxanes
9. 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
10. Bowel obstruction or motility disorder that may influence the resorption of drugs as judged by the treating physician
11. Major surgical procedures within 21 days prior to providing informed consent
12. Active acute or chronic infection, which is not controlled by appropriate medication (at the discretion of the treating physician)
13. Known positivity for Human Immunodeficiency Virus HIV-1 or HIV-2 type
14. 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)
15. 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
16. 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
17. Legal incapacity |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint for this study is:
• Radiographic Progression Free Survival (rPFS) according to PCWG3 criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Tumor assessment (following PCWG3) by PSA prior to every cycle and imaging/radiological assessment (i.e. CT/MRI + bone scan) at baseline (≤ 28 days prior to administration of study medication), every 8 weeks for first 24 weeks (i.e. during week 9, 17 and 25), thereafter every 12 weeks and at End of Treatment (EOT), according to the RECIST v1.1 and PCWG3 criteria. Both PSA response and radiological response must be confirmed either after at least 3 weeks for PSA and after 4-6 weeks for RECIST v1.1. Of note: In this randomized comparative trial, the scheduled assessments should not be affected by delays in therapy, drug holidays or any other events that might lead to imbalance in a treatment arm in the timing of disease assessment |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints (based on PCWG3-modified RECIST v1.1 criteria where applicable) are:
• Objective Response Rate (ORR)
• Disease control rate (DCR)
• Duration of response (DOR)
• Radiographic Progression Free Survival (rPFS) at 6 months according to PCWG3 criteria
• Time to progression (TTP)
• PSA response rate according to PCWG3 criteria
• Progression free survival (PFS) at 6 months
• PSA-PFS according to PCWG3 criteria
• Time to PSA progression
• Time to first skeletal event
• HRQoL as assessed by FACT global, FACT-P and FACT-taxane, Treatment Satisfaction and EQ-5D-5L questionnaire
Safety endpoints:
o Incidence and severity of adverse events (AEs) according to NCI-CTCAE criteria (version 5.0)
HRQoL endpoints:
o Health Related Quality of Life (HRQoL) as assessed by FACT global, FACT-P and FACT-taxane, Treatment Satisfaction and EQ-5D questionnaires:
o Overall HRQoL improvement
o Improvements in the individual HRQoL domains
o Time to HRQoL deterioration
o Overall Health Related Utility |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Tumour assessment => see item 5.1.1
Safety assessment: all visits
FACT global, FACT-P and FACT-taxane, Treatment Satisfaction and EQ-5D questionnaire: Baseline, cycle 3 and 6 and after 10 cycles or end of treatment |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Russian Federation |
| United States |
| Germany |
| Hungary |
| Poland |
| Czechia |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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