Improve Checkpoint-blockade Response in Advanced Urothelial Cancer

Phase 1

Completed

• Conditions: Urothelial Carcinoma
• Interventions: Drug: Tremelimumab; Drug: Durvalumab; Drug: Paclitaxel

• Registration Number: NCT03871036
• Lead Sponsor: The Netherlands Cancer Institute

Brief Summary

This trial will include metastatic urothelial carcinoma patients who progressed during or after treatment with anti-PD(L)1 therapy and have been treated by a platinum-containing regimen, or are cisplatin-ineligible. Patients will receive either paclitaxel in combination with durvalumab (anti-PDL-1) and a single dose (300 mg) of tremelimumab (anti-CTLA4), or paclitaxel with only a high dose of tremelimumab (750 mg). Tremelimumab (750 mg), without paclitaxel will be used as a comparison arm.

A run-in safety phase will be followed by a non-comparative 3-arm randomized study with a Simon's 2-stage optimal design.

Detailed Description

This trial will include metastatic urothelial carcinoma patients who progressed during or after treatment with anti-PD(L)1 therapy and have been treated by a platinum-containing regimen, or are cisplatin-ineligible.

A run-in safety phase will be followed by a non-comparative 3-arm randomized study with a Simon's 2-stage optimal design.

Screening:

Before enrollment, patients will need to complete the following screening procedures (among other assessments):

* Baseline evaluation by CT chest/abdomen/pelvis (\<4 weeks)

* Laboratory assessment

* Tissue biopsy (in at least 6 patients per arm)

Run-in phase-1 (R1): n=3 patients will be treated with:

* paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6

* tremelimumab 75 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45

Run-in phase-2 (R2): n=3 patients will be treated with:

* paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6

* tremelimumab 225 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45

Run-in phase-3 (R3): n=2 x 3 patients will be randomized over 2 arms:

* paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6

* tremelimumab 750 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45 OR

* paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6

* tremelimumab 75 mg on day 1 of cycles 2-5

* durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)

Run-in phase-4 (R4): n=3 patients will be treated with:

* paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6

* tremelimumab 300 mg once on day 1 of cycle 2

* durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)

Enrollment will start with the first run-in cohort (R1) and will be halted after inclusion of the 3rd patient, until 60 days after start of treatment of this patient. Stopping rules are defined in the section 6.3 of the protocol. In case unexpected toxicity occurs (either as defined by the stopping rules or otherwise unexpected severe toxicity), the study team will discuss with the IDMC whether expansion to include 3 additional subjects is warranted. If no unexpected toxicity has occurred within 60 days after initiation of treatment of the 3rd patient of R1, enrollment for R2 will begin in a similar fashion. If 2 or more nonhematological toxicities as described in section 6.3 "Definition of DLT" occur in R1 or R2, enrollment will be suspended until the IDMC has formulated an advice. After this advice, the sponsor will decide on continuation.

If no unexpected toxicity has occurred within 60 days after initiation of treatment of the 3rd patient of R2, the study will continue with a third run-in cohort (R3) where patients will be randomized over 2 arms (R3A and R3B), n=3 per arm. If no unexpected toxicity has occurred within 60 days after initiation of treatment of the 3rd patient in arm R3A, this arm will be continued into the main study phase (as Arm A). If unacceptable toxicity is observed at either 225 mg or 750 mg of tremelimumab during one of the run-in cohorts, a lower dose level can be used in the main study. In addition, after completion of R3A and continuation in the main study phase, a control arm (Arm C) will be initiated where patients will be treated with tremelimumab monotherapy (without paclitaxel).

If no unexpected toxicity has occurred within 60 days after initiation of treatment of the 3rd patient of R3B, enrollment for run-in cohort R4 will begin in a similar fashion as described for the earlier run-in cohorts. Expansion arms A and C will be paused while this cohort is enrolling. If no unexpected toxicity has occurred within 60 days after initiation of treatment of the 3rd patient of R4, enrollment for arm R4 will be continued into the main study phase (as Arm B). If unacceptable toxicity is observed at 300 mg of tremelimumab in combination with 1500mg durvalumab, arm B, combining paclitaxel, tremelimumab and durvalumab, will be discontinued.

Main study:

Arm A:

* paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6

* tremelimumab 750 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45

Arm B:

* paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6

* tremelimumab 300 mg once on day 1 of cycle 2

* durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)

Arm C (control arm):

• tremelimumab 750 mg on day 1 of cycles 1-5 and then every 12 weeks until week 41

Enrollment will be halted when 12 patients are enrolled in each arm; this will include patients treated in R3 and R4 at the dose level used in the main study. These patients will be included in the efficacy analysis.

After the last patient has had the second evaluation scan, the Objective Response Rate (ORR) of each treatment arm will be evaluated. If one or more of the experimental arms has ≥2 responses, the study team will discuss continuation of one of the experimental arms to n=20 with the IDMC. In case 2 responses are seen in one of the arms prior to the second evaluation scan of the last patient, a decision on expansion of that arm may be recommended earlier.

Study Timeline

• Study First Submitted: 2019-02-14
• Study First Submitted QC: 2019-03-08
• Study First Posted: 2019-03-12
• Study Start: 2019-05-01
• Primary Completion: 2023-09-07
• Study Completion: 2025-01-15
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-04
• Last Update Posted: 2025-03-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 53

Inclusion Criteria

For inclusion in the study, patients should fulfill the following criteria:

1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (eg, European Union [EU] Data Privacy Directive) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.

2. Patients with histologically or cytologically documented metastatic or irresectable (i.e. T4b, N1-3 and/or M1a/b) urothelial cell carcinoma (including renal pelvis, ureters, urinary bladder, and urethra).

3. Patients ineligible for cisplatin-based chemotherapy OR previous treatment with platinum-based chemotherapy, either in the neo-adjuvant setting or in any other setting. This is defined as progression on or after at least 2 cycles of platinum-based chemotherapy (e.g. MVAC, cisplatin/gemcitabine, carpoblatin/gemcitabine). Patients who had to stop platinum-based therapy because of toxicity after at least 2 cycles are eligible if progressive disease has been confirmed.

4. Previous treatment with anti-PD(L)1 immunotherapy. The following conditions apply for inclusion:

   1. Must not have experienced a toxicity that led to permanent discontinuation of prior anti-PD(L)1 immunotherapy;
   2. All treatment-related AEs while receiving prior anti-PD(L)1 immunotherapy must have completely resolved or resolved to baseline prior to screening for this study;
   3. Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior anti-PD(L)1 immunotherapy;
   4. Patients with endocrine AE of ≤Grade 2 are permitted to enroll if the AEs are stably maintained on appropriate replacement therapy and are asymptomatic;
   5. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of >10 mg prednisone or equivalent per day;

5. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have a Revised Clinical Study Protocol short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and that is suitable for accurate repeated measurements as per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) guidelines.

6. Age >18 years at time of study entry.

7. World Health Organisation (WHO) performance status of 0 or 1.

8. Body weight >30kg.

9. Adequate normal organ and marrow function as defined below:

   1. Haemoglobin ≥9.0 g/dL = 5.6 mmol/L;
   2. Absolute neutrophil count (ANC) ≥1.5 x 109/L;
   3. Platelet count ≥100 x 109/L;
   4. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). (Does not apply to patients with confirmed Gilbert's syndrome, who will be allowed only in consultation with the treating physician);
   5. 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;
   6. Measured creatinine clearance (CL) >30 mL/min or Calculated creatinine clearance CL>30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:

   Males:

   Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)

   Females:

   Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)

10. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal in case of amenorrhoeu for 12 months without an alternative medical cause. The following age-specific requirements apply:

    • Women <50 years of age would be considered post-menopausal in case of amenorrhea for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy);
    • Women ≥50 years of age would be considered post-menopausal in case of amenorrhea for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy);

11. 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.

12. Must have a life expectancy of at least 12 weeks

Exclusion Criteria

Patients should not enter the study if any of the following exclusion criteria are fulfilled:

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

2. Participation in another clinical study with an investigational product during the last 4 weeks.

3. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.

4. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolization, monoclonal antibodies) ≤28 days prior to the first dose of study drug.

5. Any unresolved toxicity NCI CTCAE 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 or tremelimumab may be included only after consultation with the Study Physician;
   • Toxicity caused by treatment with anti-PD(L)1 should return to baseline, except for endocrine toxicity on a stable dose of replacement therapy.

6. Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.

7. 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.

8. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.

9. History of allogenic organ transplantation.

10. 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. Psoriasis, if not treated by immunesuppressants, is allowed;
    • 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.

11. 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, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.

12. History of another primary malignancy except for:

    • Malignancy treated with curative intent and with no known active disease ≥2 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;
    • Curatively treated localized prostate cancer without PSA recurrence.

13. History of leptomeningeal carcinomatosis.

14. Brain metastases or spinal cord compression, unless radiographically stable, defined as 2 brain images, both of which are obtained after treatment to the brain metastases. These imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression. In addition, any neurologic symptoms that developed either as a result of the brain metastases or treatment thereof must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of ≤10mg/day of prednisone or its equivalent for at least 14 days prior to the start of treatment.. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry.

15. History of active primary immunodeficiency.

16. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings), 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.

17. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. 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).

18. 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.

19. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of tremelimumab, durvalumab, or durvalumab + tremelimumab combination therapy.

20. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

21. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.

22. Previous treatment with anti-CTLA-4 immunotherapy.

23. Known allergy or hypersensitivity to IP or any excipient. Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.3 of the clinical protocol. If a patient withdraws from participation in the study, then that specific enrollment/randomization code cannot be reused. Withdrawn patients will not be replaced.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tremelimumab vs Tremelimumab+Durvalumab (R3)	Tremelimumab	Run-in phase-3 (R3): n=2 x 3 patients will be randomized over 2 arms: * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 750 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45 OR * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 75 mg on day 1 of cycles 2-5 * durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)
Tremelimumab 750 (A)	Tremelimumab	Arm A: * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 750 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45
Tremelimumab 300 (R4)	Paclitaxel	Run-in phase-4 (R4): n=3 patients will be treated with: * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 300 mg once on day 1 of cycle 2 * durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)
Tremelimumab 750 (A)	Paclitaxel	Arm A: * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 750 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45
Tremelimumab+Durvalumab (B)	Tremelimumab	Arm B: * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 300 mg once on day 1 of cycle 2 * durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)
Tremelimumab 75 (R1)	Paclitaxel	Run-in phase-1 (R1): n=3 patients will be treated with: * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 75 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45
Tremelimumab 75 (R1)	Tremelimumab	Run-in phase-1 (R1): n=3 patients will be treated with: * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 75 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45
Tremelimumab 225 (R2)	Tremelimumab	Run-in phase-2 (R2): n=3 patients will be treated with: * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 225 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45
Tremelimumab 225 (R2)	Paclitaxel	Run-in phase-2 (R2): n=3 patients will be treated with: * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 225 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45
Tremelimumab vs Tremelimumab+Durvalumab (R3)	Durvalumab	Run-in phase-3 (R3): n=2 x 3 patients will be randomized over 2 arms: * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 750 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45 OR * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 75 mg on day 1 of cycles 2-5 * durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)
Tremelimumab 300 (R4)	Tremelimumab	Run-in phase-4 (R4): n=3 patients will be treated with: * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 300 mg once on day 1 of cycle 2 * durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)
Tremelimumab 300 (R4)	Durvalumab	Run-in phase-4 (R4): n=3 patients will be treated with: * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 300 mg once on day 1 of cycle 2 * durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)
Tremelimumab vs Tremelimumab+Durvalumab (R3)	Paclitaxel	Run-in phase-3 (R3): n=2 x 3 patients will be randomized over 2 arms: * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 750 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45 OR * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 75 mg on day 1 of cycles 2-5 * durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)
Tremelimumab+Durvalumab (B)	Durvalumab	Arm B: * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 300 mg once on day 1 of cycle 2 * durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)
Tremelimumab+Durvalumab (B)	Paclitaxel	Arm B: * paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6 * tremelimumab 300 mg once on day 1 of cycle 2 * durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)
Tremelimumab without paclitaxel (C)	Tremelimumab	Arm C (control arm): • tremelimumab 750 mg on day 1 of cycles 1-5 and then every 12 weeks until week 41

Primary Outcome Measures

Name	Time	Method
Overall response rate (ORR), defined as the proportion of participants whose confirmed best overall response is either a PR or CR after treatment with paclitaxel and a high dose of tremelimumab based upon the RECIST v1.1 guidelines.	Final ORR will be determined after the confirmatory scan of the last patient, which is scheduled up to 21 weeks after start of treatment of the final patient	Tumor evaluation will take place using CT-Chest and abdomen, based on the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) guidelines. The first evaluation will take place 12 weeks after initiating treatment. After this initial scan, tumor evaluation will take place every 8 weeks for the first year. After the first year, tumor evaluation will be done every 12 weeks.
Overall response rate (ORR), defined as the proportion of participants whose confirmed best overall response is either a PR or CR after treatment with paclitaxel, tremelimumab and durvalumab based upon the RECIST v1.1 guidelines.	Final ORR will be determined after the confirmatory scan of the last patient, which is scheduled up to 21 weeks after start of treatment of the final patient	Tumor evaluation will take place using CT-Chest and abdomen, based on the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) guidelines. The first evaluation will take place 12 weeks after initiating treatment. After this initial scan, tumor evaluation will take place every 8 weeks for the first year. After the first year, tumor evaluation will be done every 12 weeks.

Secondary Outcome Measures

Name	Time	Method
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0	Overall therapeutic safety will be determined 90 days after the last patient has received the last treatment dose	Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
Overall survival (OS) in months for each of the treatment strategies.	OS data will be collected up to 2 years after inclusion of the final patient	survival data will be collected every 6 months after the last study visit for each participant.
Progression-free survival (PFS) in months for each of the treatment strategies	PFS data will be collected up to 2 years after inclusion of the final patient	survival data will be collected every 6 months after the last study visit for each participant.
Duration of response in months for each of the treatment strategies	DOR data will be collected up to 2 years after inclusion of the final patient	survival data will be collected every 6 months after the last study visit for each participant.

Trial Locations

Locations (1)

Antoni van Leeuwenhoek Ziekenhuis; 🇳🇱 Amsterdam, Netherlands