Prostate cancer with OligometaSTatic relapse: Combining stereotactic Ablative Radiotherapy and Durvalumab (MEDI4736), a randomized phase II trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut De Cancerologie De L Ouest

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Male Urogenital Diseases [C12], Diseases [C] - Neoplasms [C04]

Trial duration

21 Mar 2019 → ongoing

Decision date (initial)

2024-07-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

ASTRA ZENECA

External identifiers

EU CT number

2024-513207-13-00

EudraCT number

2017-003827-31

ClinicalTrials.gov

NCT03795207

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Therapy

Two-years Progression-free survival

Secondary objectives 16

1. a) Biochemical progression-free survival
2. b) Event-free survival (EFS)
3. c) Clinical progression-free survival (cPFS)
4. d) Distant progression-free survival (dPFS)
5. e) Quality of life scoring using the EORTC QLQ-C30 supplemented with QLQ-PR25 and pain with BPI + EVA
6. f) Androgen deprivation therapy free survival
7. g) Prostate cancer specific survival (PCSS) will be calculated from randomization until Prostate cancer death or complications related to the protocol treatment
8. h) Overall survival (OS) will be calculated from randomization until death from any cause
9. i) Time to first symptomatic event will be calculated from randomization until the event of symptoms due to metastatic disease
10. j) Acute and late toxicity due to radiotherapy will be scored using the Common toxicity criteria version 5.0
11. k) Plasma biomarkers measurements
12. l) Immune response monitoring
13. m) PDL1 expression in CTCs
14. n) Time to castration resistance
15. o) Association between the PSA 3, 5, and 7-months after SBRT (in 3 classes : <0.1 ng/mL / 0.1-0.49 / >0.5 ng/mL), and dPFS, PCSS and OS (ref : PMID: 29727915, PMID: 24739897). Exploratory analyses investigating association between other PSA threshold values at different timepoints with survival outcomes will be performed
16. p) To evaluate the association between the early binary endpoint “No evidence of disease (NED)” and dPFS, PCSS and OS. NED is defined as patients meeting all of the following: - Alive - No biochemical recurrence (defined as PSA >0.5 ng/ml + nadir and rising) - No distant progression - No local progression - No subsequent therapy for PC

Conditions and MedDRA coding

oligometastatic hormone sensitive prostate cancer

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1. Written informed consent obtained from the patient prior to performing any protocol-related procedures, including screening evaluations
2. 2. Age > or = 18 years at time of study entry
3. 3. Histologically proven diagnosis of prostate cancer (PCa)
4. 4. PCa patients with a biochemical recurrence “Rising PSA” following treatment with curative intent (radical prostatectomy, primary radiotherapy or a combination of both) as defined by the EAU guidelines.
5. 5. Amended A maximum of 5 bone or lymph node metastases diagnosed on Ga-PSMA PET CT, OR a maximum of 3 bone or lymph node metastases diagnosed on FCH-PET CT o ≤ 4 cm for bone metastases o ≤ 2 cm for lymph node metastases
6. 6. WHO performance state 0-1
7. 7. Controlled primary tumor. In case the PSA > 0,2 ng/ml in the postoperative setting patients are eligible if a multiparametric MRI or PET scan of the prostate bed rules out a local relapse. Patients after primary radiotherapy should undergo MRI of the prostate according to the European Society of Urogenital Radiology (ESUR) guidelines to rule out local relapse. In case of a suspicious lesion, a biopsy should confirm local recurrence and patients should be referred for local salvage prostatectomy when distant metastases are ruled out. If MRI rules out local relapse, patients are eligible.
8. 8. If ADT has been previously administered to the patient, a minimum of 12 months must have elapsed between the predicted duration of the last injection and inclusion of the patient in the study. For this category of patients, serum testosterone has to be higher than 8.5 nmol/l prior to inclusion.
9. 9. Adequate normal organ and marrow function as defined below: o Haemoglobin ≥9.0 g/dL o Absolute neutrophil count (ANC) ≥ 1.5 x 103 /L (≥ 1500 per mm3) o Platelet count ≥ 75 x 109/L (≥75,000 per mm3) o Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), who will be allowed only in consultation with their physician. o AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN o Measured creatinine clearance (CL) ≥ 40 ml/min or Calculated creatinine CL ≥ 40 ml/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: Creatinine CL (ml/min) = Weight (kg) x (140 – Age) 72 x serum creatinine (mg/dL)
10. 10. Body weight > 30kg
11. 11. Life expectancy of > 24 months
12. 12. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
13. 13. Social insurance

Exclusion criteria 31

1. 1. Serum testosterone level < 8.5 nmol/l
2. 2. Vertebral metastases with a minimum distance inferior to 5 mm between GTV and spinal cord
3. 3. Suppressed
4. 4. Lymph nodes greater than 20 mm
5. 5. Modified Patient with PSA doubling time less than 3 months and with two metastases or more
6. 6. Spinal cord compression
7. 7. Any unresolved toxicity NCI CTCAE (5.0) Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria - Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. - Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
8. 8. PSA rise while on active treatment (LHRH-agonist, LHRH-antagonist, anti-androgen, maximal androgen blockade, oestrogen)
9. 9. Lung, Brain, Liver or other visceral metastases
10. 10. Relapsed primary tumor
11. 11. Perihilar lymphnode metastases
12. 12. Previous irradiation of the oligometastatic site using a dose > 20 Gy less than 5 years ago
13. 13. Previous treatment with a cytotoxic agent for PCa
14. 14. Treatment during the past month with products known to influence PSA levels (e.g. fluconazole, finasteride, corticosteroids...)
15. 14. Participation in another clinical study with an investigational product during the last 4 weeks
16. 16. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
17. 17. Any prior immune therapy (CTLA-4, PD1 or PD-L1 inhibitor, including durvalumab)
18. 18. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab,. The following are exceptions to this criterion:  Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent  Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
19. 19. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
20. 20. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of Durvalumab.
21. 21. History of allogenic organ transplantation
22. 22. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:  Patients with vitiligo or alopecia  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement  Any chronic skin condition that does not require systemic therapy  Patients without active disease in the last 5 years may be included but only after consultation with the study physician  Patients with celiac disease controlled by diet alone
23. 23. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement
24. 24. History of another primary malignancy except for  Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease  Adequately treated carcinoma in situ without evidence of disease
25. 25. History of leptomeningeal carcinomatosis
26. 26. History of active primary immunodeficiency
27. 27. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
28. 28. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
29. 29. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
30. 30. Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment
31. 31. Male patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 3 types of progression are defined and definitions of progression are used and registered according to the recommendations of the prostate cancer clinical trials working group. If a patient meets any of the progression criteria or death from any causes, the patient will be considered to have progressive disease. Calculation will start from randomization until progression or death. 1. PSA or biochemical progression 2. Local progression 3. Distant progression

Secondary endpoints 16

1. a) Time from randomization to the date of PSA or biochemical progression as defined above
2. b) Time from randomization to the date of any event of PSA progression, local progression, distant progression, or death
3. c) Time from randomization to the date of any event of local progression, distant progression, or death
4. d) Time from randomization to the date of any event of distant progression, or death
5. e)Quality of life scoring using the EORTC QLQ-C30 supplemented with QLQ-PR25 and pain with BPI + EVA
6. f) ADT will be started in both arms at time of polymetastatic disease, local progression of metastases (defined above) or symptoms. In case of a metachronous oligometastatic recurrence, a retreatment with radiotherapy or surgery is allowed. Calculation will start from randomization until ADT is started.
7. g) Prostate cancer specific survival (PCSS) will be calculated from randomization until Prostate cancer death or complications related to the protocol treatment
8. h) Overall survival (OS) will be calculated from randomization until death from any cause
9. Time to first symptomatic event will be calculated from randomization until the event of symptoms due to metastatic disease
10. j) Acute and late toxicity due to radiotherapy will be scored using the Common toxicity criteria version 5.0
11. k) Plasma biomarkers measurements
12. l) Immune response monitoring
13. m) PDL1 expression in CTCs
14. n) Time to castration resistance
15. o) Association between the PSA 3, 5, and 7-months after SBRT (in 3 classes : <0.1 ng/mL / 0.1-0.49 / >0.5 ng/mL), and dPFS, PCSS and OS (ref : PMID: 29727915, PMID: 24739897). Exploratory analyses investigating association between other PSA threshold values at different timepoints with survival outcomes will be performed
16. NED is defined as patients meeting all of the following: - Alive - No biochemical recurrence (defined as PSA >0.5 ng/ml + nadir and rising) - No distant progression - No local progression - No subsequent therapy for PC

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut De Cancerologie De L Ouest

Sponsor organisation

Institut De Cancerologie De L Ouest

Address

Bd Du Professeur Jacques Monod

City

St Herblain

Postcode

44800

Country

France

Scientific contact point

Organisation

Institut De Cancerologie De L Ouest

Contact name

SUPIOT

Public contact point

Organisation

Institut De Cancerologie De L Ouest

Contact name

TIGREAT

Locations

1 EU/EEA country · 16 investigational sites

By country

Investigational sites

Country notifications

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

Application history

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