Improve Checkpoint-blockade Response in Advanced Urothelial Cancer

NCT03871036 | Completed Phase 1 DMC

• 1 other identifier: M18ICR/ESR-18-13667
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

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.

Conditions

Urothelial Carcinoma

Keywords

Advanced urothelial carcinoma; Checkpoint inhibition; Tremelimumab; Durvalumab; Paclitaxel

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  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

• 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.

  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.

  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

Secondary Outcomes (4)

• 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

• 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

• 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

• 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

Other Outcomes (2)

• Determine the effects of paclitaxel +/- tremelimumab +/- durvalumab on T-cell infiltration in the tumor-immune micro-environment (TME) when comparing baseline vs on-treatment tumor biopsies.

  Tissues and samples will be collected up to 2 years after inclusion of the final patient

• Obtain a comprehensive overview of changes in the tumor micro-environment upon treatment with paclitaxel +/- tremelimumab +/- durvalumab comparing baseline and on-treatment biopsies.

  Tissues and samples will be collected up to 2 years after inclusion of the final patient

Study Arms (7)

Tremelimumab 75 (R1)

EXPERIMENTAL

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

Drug: Tremelimumab; Drug: Paclitaxel

Tremelimumab 225 (R2)

EXPERIMENTAL

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

Drug: Tremelimumab; Drug: Paclitaxel

Tremelimumab vs Tremelimumab+Durvalumab (R3)

EXPERIMENTAL

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)

Drug: Tremelimumab; Drug: Durvalumab; Drug: Paclitaxel

Tremelimumab 300 (R4)

EXPERIMENTAL

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)

Drug: Tremelimumab; Drug: Durvalumab; Drug: Paclitaxel

Tremelimumab 750 (A)

EXPERIMENTAL

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

Drug: Tremelimumab; Drug: Paclitaxel

Tremelimumab+Durvalumab (B)

EXPERIMENTAL

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)

Drug: Tremelimumab; Drug: Durvalumab; Drug: Paclitaxel

Tremelimumab without paclitaxel (C)

EXPERIMENTAL

Arm C (control arm): • tremelimumab 750 mg on day 1 of cycles 1-5 and then every 12 weeks until week 41

Drug: Tremelimumab

Interventions

Tremelimumab DRUG

See experimental arm description for more details.

Also known as: Ticilimumab, CP-675,206

Tremelimumab 225 (R2); Tremelimumab 300 (R4); Tremelimumab 75 (R1); Tremelimumab 750 (A); Tremelimumab vs Tremelimumab+Durvalumab (R3); Tremelimumab without paclitaxel (C); Tremelimumab+Durvalumab (B)

Durvalumab DRUG

See experimental arm description for more details.

Also known as: Imfinzi, MEDI4736

Tremelimumab 300 (R4); Tremelimumab vs Tremelimumab+Durvalumab (R3); Tremelimumab+Durvalumab (B)

Paclitaxel DRUG

See experimental arm description for more details.

Also known as: Taxol

Tremelimumab 225 (R2); Tremelimumab 300 (R4); Tremelimumab 75 (R1); Tremelimumab 750 (A); Tremelimumab vs Tremelimumab+Durvalumab (R3); Tremelimumab+Durvalumab (B)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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).
• 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.
• Must not have experienced a toxicity that led to permanent discontinuation of prior anti-PD(L)1 immunotherapy;
• 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;
• 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;
• Patients with endocrine AE of ≤Grade 2 are permitted to enroll if the AEs are stably maintained on appropriate replacement therapy and are asymptomatic;
• 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;
• 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.
• Age \>18 years at time of study entry.
• World Health Organisation (WHO) performance status of 0 or 1.
• Body weight \>30kg.
• Adequate normal organ and marrow function as defined below:
• Haemoglobin ≥9.0 g/dL = 5.6 mmol/L;
• Absolute neutrophil count (ANC) ≥1.5 x 109/L;

You may not qualify if:

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Participation in another clinical study with an investigational product during the last 4 weeks.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• History of allogenic organ transplantation.
• 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;

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• AstraZeneca: collaborator

Study Sites (1)

Antoni van Leeuwenhoek Ziekenhuis

Amsterdam, Netherlands

Location

MeSH Terms

Conditions

Carcinoma, Transitional Cell

Interventions

tremelimumab; durvalumab; Paclitaxel

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Michiel MS van der Heijden, MD, PhD

  NKI-AvL

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A run-in safety phase will be followed by a non-comparative 3-arm randomized study with a Simon's 2-stage optimal design. Run-in safety phase will start with an increasing dose of tremelimumab in combination with paclitaxel. In the final part of the run-in safety phase, patients will be randomized to receive paclitaxel with either regular dose tremelimumab in combination with durvalumab, or a high dose tremelimumab. If no unexpected toxicity occurs, the experimental phase of the study will start, randomizing patients over 3 arms. The best arm will be expanded based on a Simon's 2-stage optimal design.

Study Record Dates

• First Submitted: February 14, 2019
• First Posted: March 12, 2019
• Study Start: May 1, 2019
• Primary Completion: September 7, 2023
• Study Completion: January 15, 2025
• Last Updated: March 6, 2025

Record last verified: 2025-03

Locations

NL (1)