Castration-resistant Prostate Cancer, Prostate Cancer Metastatic
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGDocetaxel in Parenteral Dosage Form
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
DRUGModraDoc006/r
Treatment with twice daily once weekly (BIDW) ModraDoc006 (oral docetaxel) 10mg tablets in combination with ritonavir 100mg tablets
Sponsors
Modra Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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 radiographic Progression Free Survival (rPFS) in both groups to calculate the sample size for the pivotal study.
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Radiographic Progression Free Survival (rPFS) | Time from the date of randomization to the date of the first radiologic progression (per PCWG3 criteria) or death from any cause, whichever occurred first, an average of 1 year. | Evaluation of rPFS that will be observed as measured by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria, in patients with metastatic prostate cancer after treatment with ModraDoc006/r or docetaxel IV. Radiographic disease progression was defined by the local assessment of: * Progressive disease by RECIST v1.1. for soft tissue disease * Or the appearance of 2 or more new bone lesions on bone scan (PCWG3) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | From baseline through study completion, an average of 1 year | DOR is defined as the median time in months from documentation of first tumor response to the first objective evidence of radiologic progression, as measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT/MRI, in the subpopulation of patients experiencing a Complete Response (CR), i.e. Disappearance of all target lesions; and Partial Response (PR), i.e. ≥30% decrease in the sum of the longest diameter of target lesions. |
| PSA Response Rate | From baseline through study completion, an average of 1 year | PSA decline of \>50% from baseline with confirmatory read ≥3 weeks later, based on the Prostate Cancer Working Group 3 (PCWG3) criteria recommendations. |
| PSA-PFS | Time from the date of randomization to the date of the first prostate-specific antigen progression or death from any cause, whichever occurred first, an average of 1 year. | Prostate-Specific Antigen Progression-Free Survival (PSA-PFS) according to Prostate Cancer Working Group 3 (PCWG3) guidance. Prostate-specific antigen progression was defined as per PCWG3 guidance: * If a patient presented first a decline from baseline, progression was defined as the first PSA increase that was ≥25% and ≥2 ng/mL above the nadir, and which was confirmed by a consecutive second value ≥3 weeks later that fulfilled the same criteria (i.e., a confirmed rising trend) * If a patient did not present a decline from baseline, progression was defined as the first PSA increase that was ≥25% and ≥2 ng/mL increased from baseline beyond 12 weeks. |
| Time to PSA Progression | From baseline through study completion, an average of 1 year | Time to PSA progression was defined as the time from the date of randomization to the PSA progression as defined by Prostate Cancer Working Group 3 (PCWG3). Prostate-specific antigen progression was defined as per PCWG3 guidance: * If a patient presented first a decline from baseline, progression was defined as the first PSA increase that was ≥25% and ≥2 ng/mL above the nadir, and which was confirmed by a consecutive second value ≥3 weeks later that fulfilled the same criteria (i.e., a confirmed rising trend) * If a patient did not present a decline from baseline, progression was defined as the first PSA increase that was ≥25% and ≥2 ng/mL increased from baseline beyond 12 weeks. |
| Number of Participants Who Experienced a First Skeletal-Related Event | From baseline through study completion, an average of 1 year | Number of Participants who Experienced a first Skeletal-Related Event (SRE), i.e. 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 the time of randomisation to the first occurrence. Note: Due to small number of SREs the median time to SRE was not evaluable in this patient population. |
| Adverse Event Profile (Safety) | Evaluation of all adverse events during the complete study treatment until 28 days after the last intake, an average of 1 year. | The hematological and non-hematological safety profile of ModraDoc006/r will be assessed by clinical and laboratory evaluations according to CTCAE v5.0. |
| Overall Response Rate (ORR) | From baseline during the complete study treatment, including follow-up visit 28 days after the last treatment, an average of 1 year. | Percentage of patients evaluable for radiological response (ERR) per Prostate Cancer Working Group 3 (PCWG3)-modified Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT/MRI with best overall response of either Complete Response (CR), i.e. disappearance of all target lesions, or Partial Response (PR), i.e. ≥30% decrease in the sum of the longest diameter of target lesions. PCGW3-modified RECIST 1.1 criteria implements the requirement for confirmation of progression at least 6 weeks later for bone lesions at all measurement time points, and for soft tissue lesions after the first measurement (after 2 months) only. Tumor measurements were scheduled after every 8 treatment weeks for the first 24 weeks (i.e. during Week 9, Week 17 and Week 25) and every 12 weeks thereafter. |
| Disease Control Rate (DCR) | From baseline through study completion, an average of 1 year | Disease control rate is calculated by the percentage of patients with Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), ≥30% decrease in the sum of the longest diameter of target lesions; and Stable Disease (SD), ≤20% increase to \<30% decrease in the sum of the longest diameter of target lesions per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT/MRI. Disease control rate is presented by treatment group for patients that were evaluable for radiological response for the overall study. |
| Time to Progression (TTP) | Time from the date of randomization to the date of the first radiologic progression, an average of 1 year. | Time to Progression is defined as the time from the date of randomization to the date of the first radiologic progression per PCWG3 criteria. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Overall Health-Related Utility | Assessed from baseline to End of Cycle 10 (each cycle was 21 days) | Mean change from baseline to the End of Cycle 10 in the European Quality of Life Dimension-Five Level Scale (EQD5) is presented. For the EQD5, mobility, self-care, usual activities, pain/discomfort, and anxiety/depression were scored on a 5-point scale: no problems (1), slight problems (2), moderate problems (3), severe problems (4), and extreme problems (5). Lower scores and decreases from baseline indicate improved quality of life. A visual analog scale (VAS) was used for the patient to evaluate their health state at a particular visit; the scale was numbered from 0 (representing the worst health imaginable) to 100 (representing the best health imaginable), higher scores and increases from baseline indicate improved health. |
| World Health Organization Performance Status (Eastern Cooperative Oncology Group) at End of Treatment | Score assessed at end of treatment visit (up to 2 years). | Eastern Cooperative Oncology Group (ECOG) scores at the time of end on treatment visit are presented. 0 = Normal activity 1. = Symptoms, but nearly ambulatory 2. = Symptomatic, but in bed \<50% of the day 3. = Needs to be in bed \>50% of the day, but not bedridden 4. = Unable to get out of bed 5. = Dead |
| Summary of Improvement by Individual Health- Related Quality of Life Domains | Improvement assessed at any timepoint from baseline through to End of Cycle 10 (each cycle was 21 days) | Improvement for individual patients in Health-Related Quality of Life (HRQoL) domains was defined by a ≥3-point increase in the score of a 5 point Likert-like scale at a post-baseline assessment compared with baseline, at least once during study for Functional Assessment of Cancer Therapy (FACT)-G, -P and -T. Improvement was derived using all assessments collected per protocol schedule, i.e. Baseline, End of Cycle 3, 6 and 10 (or End of Treatment if sooner). Higher scores represent better HRQoL. FACT-G = global scale, measures four domains of HRQoL in cancer patients: Physical Well-Being (7 items; score range 0-28), Social/Family Well-Being (7 items; range 0-28), Emotional Well-Being (6 items; range 0-24), Functional Well-Being (7 items; range 0-28). Total score (range 0-108) FACT-P = prostate cancer sub scale (12 items; score range 0-48). Total score (FACT-G total score + FACT-P), range 0-156) FACT-T = taxane specific domain score (16 items, range 0 to 64), Total score (0-172) |
| Overall Health-Related Quality of Life Response | From baseline through to end of Cycle 10 (each cycle was 21 days) | An overall Health-Related Quality of Life (HRQoL) improvement was defined by a 10-point or greater increase (= lower score) in the Functional Assessment of Cancer Therapy-global (FACT-G) total score assessment at a post-baseline assessment compared with baseline, at least once during the study. The FACT-G questionnaire contains 27-items to measure four domains of HRQoL on a 5 point Likert-type scale in cancer patients: Physical Well-Being (7 items; score range 0-28), Social/Family Well-Being (7 items; score range 0-28), Emotional Well-Being (6 items; score range 0-24), Functional Well-Being (7 items; score range 0-28). Higher scores and increases from baseline indicate higher quality of life. |
Countries
Czechia, Germany, Hungary, Poland, Russia, United States
Participant flow
Recruitment details
The number of enrollment is not equal to the number of patients started, because 32 patients did not meet the inclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Docetaxel IV Patients received docetaxel at 75 mg/m2 i.v. Q3W, with dexamethasone premedication, plus 5 mg oral prednisone twice daily. | 46 |
| ModraDoc006/r Patients received ModraDoc006/r either at 30-20/200-100 mg or at 20-20/200-100 mg BIDW, plus 5 mg oral prednisone twice daily. | 46 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Evaluations missing | 3 | 6 |
| Overall Study | Not started | 2 | 0 |
Baseline characteristics
| Characteristic | Total | ModraDoc006/r | Docetaxel IV |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 70 Participants | 35 Participants | 35 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 11 Participants | 11 Participants |
| Age, Continuous | 67.4 years STANDARD_DEVIATION 6.7 | 67.0 years STANDARD_DEVIATION 6.9 | 67.8 years STANDARD_DEVIATION 6.6 |
| ECOG Performance Status at study entry Performance status 0 | 46 Participants | 29 Participants | 17 Participants |
| ECOG Performance Status at study entry Performance status 1 | 43 Participants | 15 Participants | 28 Participants |
| ECOG Performance Status at study entry Performance status 2 | 3 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 89 Participants | 45 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 88 Participants | 44 Participants | 44 Participants |
| RECIST measurable disease at study entry No | 23 Participants | 10 Participants | 13 Participants |
| RECIST measurable disease at study entry Yes | 69 Participants | 36 Participants | 33 Participants |
| Region of Enrollment Czechia | 5 participants | 2 participants | 3 participants |
| Region of Enrollment Germany | 5 participants | 3 participants | 2 participants |
| Region of Enrollment Hungary | 10 participants | 3 participants | 7 participants |
| Region of Enrollment Poland | 6 participants | 3 participants | 3 participants |
| Region of Enrollment Russia | 42 participants | 22 participants | 20 participants |
| Region of Enrollment United States | 24 participants | 13 participants | 11 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 92 Participants | 46 Participants | 46 Participants |
| Time since diagnosis of mCRPC | 13.98 Months STANDARD_DEVIATION 23.3 | 15.72 Months STANDARD_DEVIATION 29.48 | 12.24 Months STANDARD_DEVIATION 14.92 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 49 | 3 / 52 |
| other Total, other adverse events | 32 / 49 | 37 / 52 |
| serious Total, serious adverse events | 16 / 49 | 13 / 52 |
Outcome results
Primary
Radiographic Progression Free Survival (rPFS)
Evaluation of rPFS that will be observed as measured by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria, in patients with metastatic prostate cancer after treatment with ModraDoc006/r or docetaxel IV. Radiographic disease progression was defined by the local assessment of: * Progressive disease by RECIST v1.1. for soft tissue disease * Or the appearance of 2 or more new bone lesions on bone scan (PCWG3)
Time frame: Time from the date of randomization to the date of the first radiologic progression (per PCWG3 criteria) or death from any cause, whichever occurred first, an average of 1 year.
Population: All patients who received at least 1 dose of intravenous docetaxel (Cohort 1) or 1 full cycle of ModraDoc006/r (Cohort 2) and had at least 1 post-baseline tumor assessment were included in the Full Analysis Set (FAS). All patients with an rPFS event.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel IV | Radiographic Progression Free Survival (rPFS) | 11.1 Months |
| ModraDoc006/r | Radiographic Progression Free Survival (rPFS) | 9.5 Months |
p-value: 0.146595% CI: [0.56, 2.65]Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: Evaluation of all adverse events during the complete study treatment until 28 days after the last intake, an average of 1 year.
Population: The Safety Population (SAF) was used for the evaluation of safety. All patients receiving at least 1 dose of trial medication in either study arm were included in the SAF.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Docetaxel IV | Adverse Event Profile (Safety) | Treatment-related serious adverse events | 8 Participants |
| Docetaxel IV | Adverse Event Profile (Safety) | Any adverse event | 48 Participants |
| Docetaxel IV | Adverse Event Profile (Safety) | Serious adverse events leading to death | 3 Participants |
| Docetaxel IV | Adverse Event Profile (Safety) | Adverse events leading to treatment discontinuation | 12 Participants |
| Docetaxel IV | Adverse Event Profile (Safety) | Treatment-related serious adverse events leading to death | 0 Participants |
| Docetaxel IV | Adverse Event Profile (Safety) | Any treatment-related adverse event | 43 Participants |
| Docetaxel IV | Adverse Event Profile (Safety) | Serious adverse events leading to treatment discontinuation | 5 Participants |
| Docetaxel IV | Adverse Event Profile (Safety) | Serious adverse events | 16 Participants |
| ModraDoc006/r | Adverse Event Profile (Safety) | Serious adverse events leading to treatment discontinuation | 5 Participants |
| ModraDoc006/r | Adverse Event Profile (Safety) | Any adverse event | 50 Participants |
| ModraDoc006/r | Adverse Event Profile (Safety) | Any treatment-related adverse event | 43 Participants |
| ModraDoc006/r | Adverse Event Profile (Safety) | Adverse events leading to treatment discontinuation | 13 Participants |
| ModraDoc006/r | Adverse Event Profile (Safety) | Treatment-related serious adverse events | 6 Participants |
| ModraDoc006/r | Adverse Event Profile (Safety) | Serious adverse events leading to death | 3 Participants |
| ModraDoc006/r | Adverse Event Profile (Safety) | Treatment-related serious adverse events leading to death | 2 Participants |
| ModraDoc006/r | Adverse Event Profile (Safety) | Serious adverse events | 13 Participants |
Secondary
Disease Control Rate (DCR)
Disease control rate is calculated by the percentage of patients with Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), ≥30% decrease in the sum of the longest diameter of target lesions; and Stable Disease (SD), ≤20% increase to \<30% decrease in the sum of the longest diameter of target lesions per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT/MRI. Disease control rate is presented by treatment group for patients that were evaluable for radiological response for the overall study.
Time frame: From baseline through study completion, an average of 1 year
Population: Population evaluable for radiological response (ERR).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Docetaxel IV | Disease Control Rate (DCR) | 96.8 Percentage of participants analyzed |
| ModraDoc006/r | Disease Control Rate (DCR) | 88.2 Percentage of participants analyzed |
Secondary
Duration of Response (DOR)
DOR is defined as the median time in months from documentation of first tumor response to the first objective evidence of radiologic progression, as measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT/MRI, in the subpopulation of patients experiencing a Complete Response (CR), i.e. Disappearance of all target lesions; and Partial Response (PR), i.e. ≥30% decrease in the sum of the longest diameter of target lesions.
Time frame: From baseline through study completion, an average of 1 year
Population: Population evaluable for radiological response (ERR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel IV | Duration of Response (DOR) | NA Months |
| ModraDoc006/r | Duration of Response (DOR) | 4.9 Months |
Comparison: DOR is calculated in the subpopulation of subjects experiencing a response (CR or PR). Hazard Ratio \< 1 means that tested drug (ModraDoc006/r) has better outcome.p-value: 0.457695% CI: [0.39, 7.93]Log Rank
Secondary
Number of Participants Who Experienced a First Skeletal-Related Event
Number of Participants who Experienced a first Skeletal-Related Event (SRE), i.e. 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 the time of randomisation to the first occurrence. Note: Due to small number of SREs the median time to SRE was not evaluable in this patient population.
Time frame: From baseline through study completion, an average of 1 year
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Docetaxel IV | Number of Participants Who Experienced a First Skeletal-Related Event | Event | 2 participants |
| Docetaxel IV | Number of Participants Who Experienced a First Skeletal-Related Event | Censored | 44 participants |
| ModraDoc006/r | Number of Participants Who Experienced a First Skeletal-Related Event | Event | 0 participants |
| ModraDoc006/r | Number of Participants Who Experienced a First Skeletal-Related Event | Censored | 46 participants |
Secondary
Overall Response Rate (ORR)
Percentage of patients evaluable for radiological response (ERR) per Prostate Cancer Working Group 3 (PCWG3)-modified Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT/MRI with best overall response of either Complete Response (CR), i.e. disappearance of all target lesions, or Partial Response (PR), i.e. ≥30% decrease in the sum of the longest diameter of target lesions. PCGW3-modified RECIST 1.1 criteria implements the requirement for confirmation of progression at least 6 weeks later for bone lesions at all measurement time points, and for soft tissue lesions after the first measurement (after 2 months) only. Tumor measurements were scheduled after every 8 treatment weeks for the first 24 weeks (i.e. during Week 9, Week 17 and Week 25) and every 12 weeks thereafter.
Time frame: From baseline during the complete study treatment, including follow-up visit 28 days after the last treatment, an average of 1 year.
Population: Population evaluable for radiological response (ERR). Patients with measurable lesions according to RECIST v1.1, that have received at least 6 weekly administrations of ModraDoc006/r or 2 standard three-weekly cycles of i.v. docetaxel were included. Response was evaluated according to RECIST v1.1 and PCWG3 criteria.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Docetaxel IV | Overall Response Rate (ORR) | 38.7 Percentage of participants analyzed |
| ModraDoc006/r | Overall Response Rate (ORR) | 44.1 Percentage of participants analyzed |
Secondary
PSA-PFS
Prostate-Specific Antigen Progression-Free Survival (PSA-PFS) according to Prostate Cancer Working Group 3 (PCWG3) guidance. Prostate-specific antigen progression was defined as per PCWG3 guidance: * If a patient presented first a decline from baseline, progression was defined as the first PSA increase that was ≥25% and ≥2 ng/mL above the nadir, and which was confirmed by a consecutive second value ≥3 weeks later that fulfilled the same criteria (i.e., a confirmed rising trend) * If a patient did not present a decline from baseline, progression was defined as the first PSA increase that was ≥25% and ≥2 ng/mL increased from baseline beyond 12 weeks.
Time frame: Time from the date of randomization to the date of the first prostate-specific antigen progression or death from any cause, whichever occurred first, an average of 1 year.
Population: Full Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel IV | PSA-PFS | 7.7 Months |
| ModraDoc006/r | PSA-PFS | 4.9 Months |
Comparison: Difference between the cohorts is tested with Log-rank test and estimated using Univariate Cox model.~Wilcoxon test is used if proportional hazards assumption is not fulfilled. Hazard Ratio \< 1 means that tested drug (ModraDoc006/r) has better outcome.p-value: 0.253995% CI: [0.79, 2.49]Log Rank
Secondary
PSA Response Rate
PSA decline of \>50% from baseline with confirmatory read ≥3 weeks later, based on the Prostate Cancer Working Group 3 (PCWG3) criteria recommendations.
Time frame: From baseline through study completion, an average of 1 year
Population: Full Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Docetaxel IV | PSA Response Rate | 26 Participants |
| ModraDoc006/r | PSA Response Rate | 23 Participants |
Secondary
Time to Progression (TTP)
Time to Progression is defined as the time from the date of randomization to the date of the first radiologic progression per PCWG3 criteria.
Time frame: Time from the date of randomization to the date of the first radiologic progression, an average of 1 year.
Population: Full Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel IV | Time to Progression (TTP) | 11.1 Months |
| ModraDoc006/r | Time to Progression (TTP) | NA Months |
Comparison: Difference between the cohorts is tested with Log-rank test and estimated using Univariate Cox model.~Wilcoxon test is used if proportional hazards assumption is not fulfilled. Hazard Ratio \< 1 means that tested drug (ModraDoc006/r) has better outcomep-value: 0.077695% CI: [0.65, 3.48]Wilcoxon (Mann-Whitney)
Secondary
Time to PSA Progression
Time to PSA progression was defined as the time from the date of randomization to the PSA progression as defined by Prostate Cancer Working Group 3 (PCWG3). Prostate-specific antigen progression was defined as per PCWG3 guidance: * If a patient presented first a decline from baseline, progression was defined as the first PSA increase that was ≥25% and ≥2 ng/mL above the nadir, and which was confirmed by a consecutive second value ≥3 weeks later that fulfilled the same criteria (i.e., a confirmed rising trend) * If a patient did not present a decline from baseline, progression was defined as the first PSA increase that was ≥25% and ≥2 ng/mL increased from baseline beyond 12 weeks.
Time frame: From baseline through study completion, an average of 1 year
Population: Full Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel IV | Time to PSA Progression | 7.7 Months |
| ModraDoc006/r | Time to PSA Progression | 4.9 Months |
Comparison: Difference between the cohorts is tested with Log-rank test and estimated using Univariate Cox model.~Wilcoxon test is used if proportional hazards assumption is not fulfilled. Hazard Ratio \< 1 means that tested drug (ModraDoc006/r) has better outcome.p-value: 0.306295% CI: [0.76, 2.42]Wilcoxon (Mann-Whitney)
Other Pre-specified
Overall Health-Related Quality of Life Response
An overall Health-Related Quality of Life (HRQoL) improvement was defined by a 10-point or greater increase (= lower score) in the Functional Assessment of Cancer Therapy-global (FACT-G) total score assessment at a post-baseline assessment compared with baseline, at least once during the study. The FACT-G questionnaire contains 27-items to measure four domains of HRQoL on a 5 point Likert-type scale in cancer patients: Physical Well-Being (7 items; score range 0-28), Social/Family Well-Being (7 items; score range 0-28), Emotional Well-Being (6 items; score range 0-24), Functional Well-Being (7 items; score range 0-28). Higher scores and increases from baseline indicate higher quality of life.
Time frame: From baseline through to end of Cycle 10 (each cycle was 21 days)
Population: Full Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Docetaxel IV | Overall Health-Related Quality of Life Response | 15 Participants |
| ModraDoc006/r | Overall Health-Related Quality of Life Response | 15 Participants |
Other Pre-specified
Overall Health-Related Utility
Mean change from baseline to the End of Cycle 10 in the European Quality of Life Dimension-Five Level Scale (EQD5) is presented. For the EQD5, mobility, self-care, usual activities, pain/discomfort, and anxiety/depression were scored on a 5-point scale: no problems (1), slight problems (2), moderate problems (3), severe problems (4), and extreme problems (5). Lower scores and decreases from baseline indicate improved quality of life. A visual analog scale (VAS) was used for the patient to evaluate their health state at a particular visit; the scale was numbered from 0 (representing the worst health imaginable) to 100 (representing the best health imaginable), higher scores and increases from baseline indicate improved health.
Time frame: Assessed from baseline to End of Cycle 10 (each cycle was 21 days)
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Docetaxel IV | Overall Health-Related Utility | Pain/discomfort | 0.4 Change of score on a scale | Standard Deviation 1.3 |
| Docetaxel IV | Overall Health-Related Utility | Self-care | 0.3 Change of score on a scale | Standard Deviation 1.1 |
| Docetaxel IV | Overall Health-Related Utility | Anxiety/depression | 0.0 Change of score on a scale | Standard Deviation 0.8 |
| Docetaxel IV | Overall Health-Related Utility | Mobility | 0.4 Change of score on a scale | Standard Deviation 1.1 |
| Docetaxel IV | Overall Health-Related Utility | Health state | -9.4 Change of score on a scale | Standard Deviation 22.2 |
| Docetaxel IV | Overall Health-Related Utility | Usual activities | 0.5 Change of score on a scale | Standard Deviation 1.3 |
| ModraDoc006/r | Overall Health-Related Utility | Health state | -5.9 Change of score on a scale | Standard Deviation 20.5 |
| ModraDoc006/r | Overall Health-Related Utility | Mobility | 0.4 Change of score on a scale | Standard Deviation 1 |
| ModraDoc006/r | Overall Health-Related Utility | Self-care | 0.0 Change of score on a scale | Standard Deviation 0.7 |
| ModraDoc006/r | Overall Health-Related Utility | Pain/discomfort | 0.1 Change of score on a scale | Standard Deviation 0.7 |
| ModraDoc006/r | Overall Health-Related Utility | Anxiety/depression | 0.0 Change of score on a scale | Standard Deviation 0.8 |
| ModraDoc006/r | Overall Health-Related Utility | Usual activities | 0.1 Change of score on a scale | Standard Deviation 0.9 |
Other Pre-specified
Summary of Improvement by Individual Health- Related Quality of Life Domains
Improvement for individual patients in Health-Related Quality of Life (HRQoL) domains was defined by a ≥3-point increase in the score of a 5 point Likert-like scale at a post-baseline assessment compared with baseline, at least once during study for Functional Assessment of Cancer Therapy (FACT)-G, -P and -T. Improvement was derived using all assessments collected per protocol schedule, i.e. Baseline, End of Cycle 3, 6 and 10 (or End of Treatment if sooner). Higher scores represent better HRQoL. FACT-G = global scale, measures four domains of HRQoL in cancer patients: Physical Well-Being (7 items; score range 0-28), Social/Family Well-Being (7 items; range 0-28), Emotional Well-Being (6 items; range 0-24), Functional Well-Being (7 items; range 0-28). Total score (range 0-108) FACT-P = prostate cancer sub scale (12 items; score range 0-48). Total score (FACT-G total score + FACT-P), range 0-156) FACT-T = taxane specific domain score (16 items, range 0 to 64), Total score (0-172)
Time frame: Improvement assessed at any timepoint from baseline through to End of Cycle 10 (each cycle was 21 days)
Population: Full Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Docetaxel IV | Summary of Improvement by Individual Health- Related Quality of Life Domains | ≥3 for FACT-G physical well-being | 9 Participants |
| Docetaxel IV | Summary of Improvement by Individual Health- Related Quality of Life Domains | ≥3 for FACT-G social or family well being | 16 Participants |
| Docetaxel IV | Summary of Improvement by Individual Health- Related Quality of Life Domains | ≥3 for FACT-G emotional well-being | 23 Participants |
| Docetaxel IV | Summary of Improvement by Individual Health- Related Quality of Life Domains | ≥3 for FACT-G functional well-being | 18 Participants |
| Docetaxel IV | Summary of Improvement by Individual Health- Related Quality of Life Domains | ≥3 for FACT-P | 21 Participants |
| Docetaxel IV | Summary of Improvement by Individual Health- Related Quality of Life Domains | ≥3 for FACT-T specific items | 19 Participants |
| ModraDoc006/r | Summary of Improvement by Individual Health- Related Quality of Life Domains | ≥3 for FACT-P | 23 Participants |
| ModraDoc006/r | Summary of Improvement by Individual Health- Related Quality of Life Domains | ≥3 for FACT-G physical well-being | 13 Participants |
| ModraDoc006/r | Summary of Improvement by Individual Health- Related Quality of Life Domains | ≥3 for FACT-G functional well-being | 21 Participants |
| ModraDoc006/r | Summary of Improvement by Individual Health- Related Quality of Life Domains | ≥3 for FACT-G social or family well being | 16 Participants |
| ModraDoc006/r | Summary of Improvement by Individual Health- Related Quality of Life Domains | ≥3 for FACT-T specific items | 23 Participants |
| ModraDoc006/r | Summary of Improvement by Individual Health- Related Quality of Life Domains | ≥3 for FACT-G emotional well-being | 18 Participants |
Other Pre-specified
World Health Organization Performance Status (Eastern Cooperative Oncology Group) at End of Treatment
Eastern Cooperative Oncology Group (ECOG) scores at the time of end on treatment visit are presented. 0 = Normal activity 1. = Symptoms, but nearly ambulatory 2. = Symptomatic, but in bed \<50% of the day 3. = Needs to be in bed \>50% of the day, but not bedridden 4. = Unable to get out of bed 5. = Dead
Time frame: Score assessed at end of treatment visit (up to 2 years).
Population: Safety population (SAF)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Docetaxel IV | World Health Organization Performance Status (Eastern Cooperative Oncology Group) at End of Treatment | ECOG Score 0 | 10 Participants |
| Docetaxel IV | World Health Organization Performance Status (Eastern Cooperative Oncology Group) at End of Treatment | ECOG Score 1 | 16 Participants |
| Docetaxel IV | World Health Organization Performance Status (Eastern Cooperative Oncology Group) at End of Treatment | ECOG Score 2 | 4 Participants |
| Docetaxel IV | World Health Organization Performance Status (Eastern Cooperative Oncology Group) at End of Treatment | ECOG Score 3 | 0 Participants |
| Docetaxel IV | World Health Organization Performance Status (Eastern Cooperative Oncology Group) at End of Treatment | ECOG Score 4 | 0 Participants |
| Docetaxel IV | World Health Organization Performance Status (Eastern Cooperative Oncology Group) at End of Treatment | ECOG Score 5 | 2 Participants |
| ModraDoc006/r | World Health Organization Performance Status (Eastern Cooperative Oncology Group) at End of Treatment | ECOG Score 4 | 0 Participants |
| ModraDoc006/r | World Health Organization Performance Status (Eastern Cooperative Oncology Group) at End of Treatment | ECOG Score 0 | 17 Participants |
| ModraDoc006/r | World Health Organization Performance Status (Eastern Cooperative Oncology Group) at End of Treatment | ECOG Score 3 | 1 Participants |
| ModraDoc006/r | World Health Organization Performance Status (Eastern Cooperative Oncology Group) at End of Treatment | ECOG Score 1 | 13 Participants |
| ModraDoc006/r | World Health Organization Performance Status (Eastern Cooperative Oncology Group) at End of Treatment | ECOG Score 5 | 1 Participants |
| ModraDoc006/r | World Health Organization Performance Status (Eastern Cooperative Oncology Group) at End of Treatment | ECOG Score 2 | 3 Participants |