Clinical trial NCT04028388: ModraDoc006/r vs Docetaxel IV in Metastatic Prostate Cancer
Official title: A Multicentre Phase 2b 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prostate Cancer Metastatic
Castration-resistant Prostate Cancer
Lead sponsor: Modra Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2019-07-22
Enrollment: 135
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Radiographic Progression Free Survival (rPFS)
timeFrame: 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.
Secondary outcomes:
measure: Adverse Event Profile (Safety)
timeFrame: Evaluation of all adverse events during the complete study treatment until 28 days after the last intake, an average of 1 year.
measure: Overall Response Rate (ORR)
timeFrame: From baseline during the complete study treatment, including follow-up visit 28 days after the last treatment, an average of 1 year.
measure: Disease Control Rate (DCR)
timeFrame: From baseline through study completion, an average of 1 year
measure: Duration of Response (DOR)
timeFrame: From baseline through study completion, an average of 1 year
measure: Time to Progression (TTP)
timeFrame: Time from the date of randomization to the date of the first radiologic progression, an average of 1 year.
measure: PSA Response Rate
timeFrame: From baseline through study completion, an average of 1 year
measure: PSA-PFS
timeFrame: 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.
measure: Time to PSA Progression
timeFrame: From baseline through study completion, an average of 1 year
measure: Number of Participants Who Experienced a First Skeletal-Related Event
timeFrame: From baseline through study completion, an average of 1 year
Other outcomes:
measure: Overall Health-Related Quality of Life Response
timeFrame: From baseline through to end of Cycle 10 (each cycle was 21 days)
measure: Summary of Improvement by Individual Health- Related Quality of Life Domains
timeFrame: Improvement assessed at any timepoint from baseline through to End of Cycle 10 (each cycle was 21 days)
measure: Overall Health-Related Utility
timeFrame: Assessed from baseline to End of Cycle 10 (each cycle was 21 days)
measure: World Health Organization Performance Status (Eastern Cooperative Oncology Group) at End of Treatment
timeFrame: Score assessed at end of treatment visit (up to 2 years).
Locations:
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Portland
country: United States
facility: Providence Cancer Institute
state: Oregon
city: Myrtle Beach
country: United States
facility: Carolina Urologic Research Center
state: South Carolina
city: Liberec
country: Czechia
facility: Nemocnice Liberec
city: Prague
country: Czechia
facility: Urologicke oddeleni FTN
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen
city: Nürtingen
country: Germany
facility: Studienpraxis Urologie
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Budapest
country: Hungary
facility: Orszagos Onkologiai Intezet (National Institute of Oncology)
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Központ
city: Győr
country: Hungary
facility: Petz Aladár Megyei Oktató Kórház
city: Szolnok
country: Hungary
facility: Jasz-Nagykun-Szolnok Megyei - Hetenyi Geza Korhaz - Rendelointezet - Onkologiai Kozpont
city: Konin
country: Poland
facility: Przychodnia Lekarska "KOMED"
city: Warszawa
country: Poland
facility: Centrum Onkologii - Instytut im. Marii Skłodowskiej-Curie
city: Łódź
country: Poland
facility: Instytut Centrum Zdrowia Matki Polki
city: Barnaul
country: Russian Federation
facility: Regional State Budgetary Healthcare Institution "Altai regional oncology dispensary"
city: Chelyabinsk
country: Russian Federation
facility: Limited Liability Company "EVIMED
city: Ekaterinburg
country: Russian Federation
facility: Sverdlovsk Regional Clinical Hospital No. 1
city: Krasnoyarsk
country: Russian Federation
facility: Regional State Budget Institution "Krasnoyarsk Territorial Clinical Hospital n.a. A.I.Kryzhanovskogo"
city: Moscow
country: Russian Federation
facility: Federal State Institution "Russian Cancer Research Center named after N. N. Blokhin" RAMS
city: Novosibirsk
country: Russian Federation
facility: CJSC Medical Center "AVICENNA"
city: Obninsk
country: Russian Federation
facility: 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
city: Omsk
country: Russian Federation
facility: Clinical Oncological Dispensary of Omsk Region
city: Saint Petersburg
country: Russian Federation
facility: Leningrad Region Onco Dispensary
city: Saint Petersburg
country: Russian Federation
facility: Limited Liability Company "Klinika Andros [Andros Clinic]"
city: Saint Petersburg
country: Russian Federation
facility: National medical research center of oncology n.a. N.N. Petrov
city: Saint Petersburg
country: Russian Federation
facility: Pavlov First Saint Petersburg State Medical University
Study officials:
affiliation: Modra Pharmaceuticals
name: M Keessen, MSc, MBA
role: STUDY_DIRECTOR
References: