DORA Trial: Phase III Trial of Docetaxel vs. Docetaxel and Radium-223 for Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Memorial Sloan Kettering Cancer Center

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

31 Jan 2019 → ongoing

Decision date (initial)

2024-10-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Bayer Healthcare LLC (United States)

External identifiers

EU CT number

2024-513867-19-00

EudraCT number

2018-002944-10

ClinicalTrials.gov

NCT03574571

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

Compare overall survival for subjects treated with docetaxel versus subjects treated with
docetaxel plus Radium-223

Secondary objectives 1

1. To compare: a. Radiographic PFS as defined in Prostate Cancer Working Group 3 (PCWG3) criteria2 b. SSE free survival c. Time to total ALP progression d. On-treatment alterations in QOL as assessed by FACT-P, BPI, and BFI measures between subjects who receive docetaxel with those who receive docetaxel and Radium-223 To determine if there is excessive: e. Febrile neutropenia in subjects treated with docetaxel plus Radium-223 f. Treatment discontinuation in subjects who are on their fourth line of therap

Conditions and MedDRA coding

metastatic Castration-Resistant Prostate Cancer (mCRPC)

Study design 4 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Willing and able to provide, or have a legally authorized representative provide, written informed consent (ICF) and HIPAA authorization for the release of personal health information. A signed ICF must be obtained before screening procedures are performed. NOTE: HIPAA authorization may be either included in the ICF or obtained separately
2. Males 18 years of age and abov
3. Histological or cytological proof of prostate cancer
4. Documented progressive mCRPC based on at least one of the following criteria: a) PSA progression defined as a minimum of 2 rising PSA levels with a minimum of a 1 week interval between each determination. A minimum PSA of 1.0 ng/mL is required for study entry. b) Soft-tissue progression defined as an increase ≥ 20% in the sum of the longest diameter (LD) of all target lesions based on the smallest sum LD since treatment started or the appearance of one or more new lesions. c) Progression of bone disease (evaluable disease) by two or more new bone lesions by bone scan
5. Two or more bone lesions defined by nuclear bone scan
6. ECOG of 0 or 1 (Appendix A: Performance Status Criteria)
7. Normal organ function with acceptable initial laboratory values within 14 days of randomization
8. Subjects must agree to use a medically acceptable method of birth control (e.g., spermicide in conjunction with a barrier such as a condom) or sexual abstinence for the duration of the study, including 6 months after the last dose of study drug. Sperm donation is prohibited during the study and for 6 months after the last dose of study drug. Female partners must use hormonal or barrier contraception unless postmenopausal or abstinent
9. Serum testosterone < 50 ng/dL. Subjects must continue primary androgen deprivation with an LHRH analogue (agonist or antagonist) if they have not undergone orchiectomy
10. All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 1 or less
11. Willing and able to comply with the protocol, including follow-up visits and examinations

Exclusion criteria 18

1. Received any other investigational therapeutic agents or other anticancer therapies within 2 weeks or 5 half-lives, whichever is shorter, prior to randomization. Note: If this requirement to have a washout of 2 weeks or 5 half-lives prior to randomization causes potential treatment delay due to Radium-223 importation timelines, the PCCTC must be contacted to request approval to randomize the subject prior to the completion of the washout. Requests for early randomization must be accompanied by written assurance by the site that the washout will be completed prior to treatment start.
2. Received external beam radiotherapy (EBRT) within the 2 weeks prior to randomization. Note: If prolonging randomization to complete EBRT washout causes potential treatment delay due to Radium-223 importation timelines, the PCCTC must be contacted to request approval to randomize the subject prior to the completion of the washout. Requests for early randomization must be accompanied by written assurance by the site that the washout will be completed prior to treatment start
3. Has an immediate need for EBRT.
4. Has received any other systemic investigational or anti-cancer radiopharmaceutical in the past
5. Has received any prostate cancer directed chemotherapy in the castration resistant setting
6. Has received > 6 prior doses of docetaxel in the castration sensitive setting. Subjects who have received up to 6 prior doses of docetaxel in the castration sensitive setting are permitted if they have not experienced disease progression within 36 weeks of last treatment with docetaxel
7. Has received four or more systemic anticancer regimens for mCRPC
8. Has known Grade ≥3 non-hematological docetaxel-related toxicities or docetaxel toxicity related dose interruption or discontinuation
9. Has received blood transfusions or growth factors within the last 4 weeks prior to randomization.
10. Symptomatic nodal disease (i.e., scrotal, penile, or leg edema)
11. Has visceral metastases with > 3 lung and/or liver metastases or individual lesion >2 cm, as assessed by CT scan or MRI of the chest/abdomen/pelvis within the last 8 weeks prior to randomization
12. Symptomatic loco-regional disease that causes ongoing Grade 3 or Grade 4 urinary or rectal symptoms
13. Subjects with a second malignancy with a risk of recurrence >30% within the next 3 years. Non-melanoma skin cancers, non-invasive bladder cancers, and other in-situ or non-invasive malignancies are permitted while on study
14. Has imminent or established cord compression based on clinical findings and/or MRI
15. Known bone marrow dysplasia
16. Has received any of the following in the 4 weeks prior to randomization: 5-alphareductase inhibitors, natural hormonally active foods (e.g., phytoestrogens) or other food supplements known to alter PSA in humans
17. Is receiving ongoing treatment with herbal medications that are known in humans to alter PSA or the natural history of prostate cancer. Subjects must discontinue any such herbal medications prior to the first dose of study drug
18. Any other serious illness or medical condition that would, in the opinion of the Investigator, make this protocol unreasonably hazardous, including but not limited to: • Uncontrolled infection • NYHA III or IV heart failure • Crohn’s disease or those with ulcerative colitis who have not undergone a colectomy • Known active infection with HIV, Hepatitis B or Hepatitis C

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The OS comparison between treatments will be evaluated at each interim analysis and the final analysis using the stratified logrank test. The stratification factors are: 1. Prior docetaxel for castration-sensitive disease (Yes or No) 2. Visceral disease (presence or absence)

Secondary endpoints 8

1. Time to event endpoints will be analyzed using a stratified logrank test with the same stratification factors. Kaplan-Meier estimates of SSE-free survival and radiographic PFS will be computed. The cumulative incidence function will be used to compute probabilities for the time to first skeletal related event and the time to ALP progression. All time to event probability estimates will be calculated within treatment.
2. Total ALP response will be compared between the treatment groups using a CMH test adjusting for the randomization strata
3. Time to maximum % post-therapy decrease in PSA will be summarized using descriptive statistics
4. Maximum % decrease in PSA will be summarized using descriptive statistics (e.g., mean, standard deviation, median, minimum, and maximum)
5. Longitudinal kernel smoothing methods will be used to estimate the PSA, bone marker, BSI, CTC, and ctDNA trajectories over time. Joint modeling will used to evaluate these trajectories with respect to OS
6. PROs will include scores from the QOL questionnaires: FACT-P, BPI, and BFI. The QOLs will be administered at baseline, week 19, Safety Follow Up, and Follow Up visits every 3 months for 1 year from last dose of either study drug. The scorespecific area under the curve (with respect to time) will be derived for each subject and these area-under-curve (AUCs) will be compared between treatments.
7. The number and percentage of febrile neutropenia in subjects treated with docetaxel plus Radium-223
8. The percentage of treatment discontinuation in subjects who are on their fourth line of therapy will be calculated by treatment arm and total

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Memorial Sloan Kettering Cancer Center

Sponsor organisation

Memorial Sloan Kettering Cancer Center

Address

1275 York Avenue

City

New York

Postcode

10065-6007

Country

United States

Scientific contact point

Organisation

Memorial Sloan Kettering Cancer Center

Contact name

Michael J. Morris

Public contact point

Organisation

Memorial Sloan Kettering Cancer Center

Contact name

Michael J. Morris

Third parties 8

Locations

2 EU/EEA countries · 24 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications