ModraDoc006/r vs Docetaxel IV in Metastatic Prostate Cancer

Phase 2

Completed

Conditions: Prostate Cancer Metastatic
Castration-resistant Prostate Cancer

Interventions: Drug: ModraDoc006/r
Drug: Docetaxel in Parenteral Dosage Form

Registration Number: NCT04028388

Lead Sponsor: Modra Pharmaceuticals

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 135

Inclusion Criteria

Age ≥ 18 years
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
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:
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).
World Health Organisation Performance Status (WHO-PS) 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), 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
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 (HBC), 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ModraDoc006/r	ModraDoc006/r	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.
Docetaxel IV	Docetaxel in Parenteral Dosage Form	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.
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.
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.
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.
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.

Trial Locations

Locations (28): Studienpraxis Urologie
🇩🇪
Nürtingen, Germany
Universitätsklinikum Tübingen
🇩🇪
Tübingen, Germany
Jasz-Nagykun-Szolnok Megyei - Hetenyi Geza Korhaz - Rendelointezet - Onkologiai Kozpont
🇭🇺
Szolnok, Hungary
Centrum Onkologii - Instytut im. Marii Skłodowskiej-Curie
🇵🇱
Warszawa, Poland
Leningrad Region Onco Dispensary
🇷🇺
Saint Petersburg, Russian Federation
Universitätsmedizin Göttingen
🇩🇪
Göttingen, Germany
Sverdlovsk Regional Clinical Hospital No. 1
🇷🇺
Ekaterinburg, Russian Federation
Instytut Centrum Zdrowia Matki Polki
🇵🇱
Łódź, Poland
Federal state budget institution "National medical research radiological center " of the Ministry of healthcare of the Russian Federation, branch - A. Tsyb Medical Radiological Research Center
🇷🇺
Obninsk, Russian Federation
Limited Liability Company "EVIMED
🇷🇺
Chelyabinsk, Russian Federation
Petz Aladár Megyei Oktató Kórház
🇭🇺
Győr, Hungary
Przychodnia Lekarska "KOMED"
🇵🇱
Konin, Poland
Limited Liability Company "Klinika Andros [Andros Clinic]"
🇷🇺
Saint Petersburg, Russian Federation
Pavlov First Saint Petersburg State Medical University
🇷🇺
Saint Petersburg, Russian Federation
Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Comprehensive Cancer Centers of Nevada
🇺🇸
Las Vegas, Nevada, United States
Providence Cancer Institute
🇺🇸
Portland, Oregon, United States
Nemocnice Liberec
🇨🇿
Liberec, Czechia
Debreceni Egyetem Klinikai Központ
🇭🇺
Debrecen, Hungary
Urologicke oddeleni FTN
🇨🇿
Prague, Czechia
Orszagos Onkologiai Intezet (National Institute of Oncology)
🇭🇺
Budapest, Hungary
Federal State Institution "Russian Cancer Research Center named after N. N. Blokhin" RAMS
🇷🇺
Moscow, Russian Federation
Regional State Budget Institution "Krasnoyarsk Territorial Clinical Hospital n.a. A.I.Kryzhanovskogo"
🇷🇺
Krasnoyarsk, Russian Federation
National medical research center of oncology n.a. N.N. Petrov
🇷🇺
Saint Petersburg, Russian Federation
Carolina Urologic Research Center
🇺🇸
Myrtle Beach, South Carolina, United States
CJSC Medical Center "AVICENNA"
🇷🇺
Novosibirsk, Russian Federation
Clinical Oncological Dispensary of Omsk Region
🇷🇺
Omsk, Russian Federation
Regional State Budgetary Healthcare Institution "Altai regional oncology dispensary"
🇷🇺
Barnaul, Russian Federation