Avelumab Plus Carboplatin-gemcitabine in Urothelial Carcinoma (INDUCOMAIN)

Phase II Multicentre, Randomized, Open-label Study to Evaluate the Safety and Efficacy of Avelumab With Gemcitabine/Carboplatin Versus Gemcitabine/Carboplatin Alone in Patients With Unresectable or Metastatic Urothelial Carcinoma (UC) Who Have Not Received Prior Systemic Therapy and Who Are Ineligible to Receive Cisplatin-based Therapy.

Phase II Multicentre, randomized, open-label study to evaluate the safety and efficacy of avelumab with gemcitabine/carboplatin versus gemcitabine/carboplatin alone in patients with unresectable or metastatic urothelial carcinoma (UC) who have not received prior systemic therapy and who are ineligible to receive cisplatin-based therapy.

Study Overview

• Status: Completed
• Conditions: Metastatic Urothelial Cancer
• Intervention / Treatment: Combination product: avelumab 10mg/kg with carboplatin/gemcitabine; Combination product: carboplatin/gemcitabine alone

Detailed Description

The aim of this study is to evaluate if the response rates (complete response [CR] + partial response [PR]) are sufficiently high and the severe acute toxicity rates acceptably low. Patients must be cisplatin-ineligible as defined by consensus criteria (see Inclusion criteria). Patients who experience disease progression >12 months following completion of a platinum-based adjuvant or neoadjuvant regimen will also be eligible for enrolment into the study.

Once it is confirmed that the subjects fulfil the eligibility criteria and have signed the informed consent form, they will be randomized in a 1:1 ratio to receive avelumab in combination with gemcitabine/carboplatin or gemcitabine/carboplatin alone as follows:

• Arm A: patients will receive 2 cycles of induction avelumab 10mg/kg every 2 weeks followed by 6 cycles of carboplatin/gemcitabine plus avelumab (carboplatin 5AUC day +1, gemcitabine 1000mg/m2 day +1 and +8 and avelumab 10mg/kg day +15) every 3 weeks followed by avelumab monotherapy 10mg/kg every 2 weeks until progressive disease or intolerance.
• Arm B: patients will receive 6 cycles of carboplatin/gemcitabine (carboplatin 5AUC day +1, gemcitabine 1000mg/m2 day +1 and +8) every 3 weeks.

Random assignment of treatment will be stratified by the presence or absence of visceral metastasis and ECOG < 2 versus ECOG 2.

All the patients enrolled in avelumab arm will receive avelumab monotherapy maintenance until disease progression or intolerable/unacceptable toxicity. Patients in the carboplatin-gemcitabine arm, will receive up to six cycles of treatment. Tumour evaluations will be scheduled every 6 weeks (±2 weeks) during carboplatin-gemcitabine treatment (in case of cycle delay this tumour evaluations every 6 weeks should be maintained to avoid any bias in the assessment of date of progression with appropriate imaging studies for response evaluation) and every 9 weeks thereafter until progressive disease (during this period, patients at arm A will be receiving avelumab maintenance treatment).

Patients with disease progression during the treatment phase will be withdrawn from the study and will receive their treatment according to the investigator's judgment and monitored to evaluate OS.

If a patient withdraws consent and refuses to receive more treatment, the patient must be followed up for survival. If a patient withdraws consent and refuses to continue in the study, the follow-up evaluations must be discontinued.

If at the moment of end of study there would be any patient still on maintenance treatment with avelumab, Sponsor will have commitment to provide the study drug in case patient is having clinical benefit.

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08003
    • Hospital del Mar
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain, 08025
    • Hospital de La Santa Creu I Sant Pau
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28026
    • Hospital Universitario 12 de Octubre
  • Murcia, Spain, 30008
    • Hospital General Universitario Morales Meseguer
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocío
  • Valencia, Spain, 46009
    • Fundacion Instituto Valenciano de Oncologia
  • Alicante
    • Elche, Alicante, Spain, 03203
      • Hospital General Universitario de Elche
  • Barcelona
    • L'Hospitalet De Llobregat, Barcelona, Spain, 08907
      • Instituto Catalán de Oncología (ICO L'Hospitalet) - H. Durán i Reynals
    • Manresa, Barcelona, Spain, 08243
      • Fundación Althaia - Xarxa Assistencial Univ. de Manresa
    • Sabadell, Barcelona, Spain, 08208
      • Hospital Universitario Parc Tauli
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Clinica Universidad de Navarra

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. The patient has given written informed consent stating that he or she understands the purpose of the study and the procedures involved and agrees to participate in the study.
2. The patient has histologically confirmed unresectable UC (T4b, any N; or any T, N2-3) or metastatic (M1, Stage IV) UC of the urinary tract, including renal pelvis, ureters, urinary bladder, and urethra
3. No prior systemic therapy for inoperable locally advanced or metastatic UC. For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo radiation for UC, a treatment-free interval >12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment naive in the metastatic setting.

4. Ineligible ("unfit") for cisplatin-based chemotherapy as defined by any one of the following criteria:

   1. Impaired renal function (GFR <60 mL/min)
   2. ECOG performance status of 2
   3. Grade ≥2 hearing loss (measured by audiometry) or ≥25 dB at two contiguous frequencies
   4. Grade ≥2 peripheral neuropathy * Criteria 4a and b are mutually exclusive: those patients with ECOG 2 won't be allowed to have an impaired renal function. For rest of the criteria, several of them may coexist.
5. The patient has at least one measurable tumour lesion (measurable disease, as defined by the RECIST criteria v1.1). If all sites of measurable disease have been irradiated, one site must have demonstrated growth after irradiation.
6. Age ≥18 years.
7. ECOG PS 0-2.
8. Life expectancy of at least 12 weeks.

9. Adequate hematologic, hepatic, and renal function, defined by:

   1. Platelet count ≥100 x10^9/L.
   2. Hemoglobin ≥ 9 g/dL (may have been transfused).
   3. Absolute neutrophil count (ANC) ≥1.5x10^9/L.

   4. Serum creatinine value not clinically significant; if creatinine >1.5 times the upper limit of normality (ULN), creatinine clearance will be calculated according to Chronic Kidney Disease Epidemiology group (CKD-EPI) formula or local formula and patients with creatinine clearance <30 mL/min shall be excluded.

      NOTE: The CKD-EPI formula for creatinine clearance is as follows:

      GFR = 141 x min(Scr/κ,1)^α x max(Scr/κ,1)^-1.209 x 0.993^Age x 1.018 [if female] x 1.159 [if black].

      Where Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1.

   5. Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT) and alkaline phosphatase (AP) ≤2.5 ×ULN (≤5 ×ULN in the presence of liver metastasis), unless this AP increase is explained due to the presence of bone metastases (with patient matching ALT, AST and bilirubin criteria), and serum total bilirubin ≤1.5 ×ULN.
10. Archival or newly-obtained representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks must be available.
11. Females of childbearing potential must have a negative serum pregnancy test within 7 days of study entry. Patients of childbearing potential who participate in this study must use effective contraceptive methods (e.g., abstinence, intrauterine device, oral or injectable contraceptives, a double barrier method or surgical sterility) to prevent pregnancy starting as soon as the informed consent form is signed and continuing for at least 13 weeks after the last dose of the study medication is administered.

Exclusion Criteria:

1. Women who are currently pregnant or breast-feeding.
2. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable.
3. Patients who had undergone major surgery, radiation therapy or treatment with chemotherapy or any investigational agent within 28 days prior to Study day 1.
4. Evidence of severe or uncontrolled systemic disease or any concurrent condition (including uncontrolled diabetes mellitus) which in the Investigator's opinion makes it undesirable for the subject to participate in the study or which would jeopardize compliance with the protocol.
5. History of another neoplasm. However, patients with prior history of either non-metastatic non melanoma skin cancers; carcinoma in situ of the cervix; or cancer cured by surgery, small field radiation or chemotherapy ≥3 years prior to randomisation; or treated patients with early stage and low risk prostate cancer (≤pT2 N0 M0, Gleason ≤6 and Prostate-specific antigen [PSA] ≤0.5 ng/mL) at study entry will be eligible.
6. Prior allogeneic stem cell or solid organ transplantation, or active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. However, patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible

7. Current use of immunosuppressive medication, EXCEPT for the following:

   1. Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
   2. Systemic corticosteroids at doses ≤10 mg/day of prednisone or equivalent;
   3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
8. History of pulmonary fibrosis.
9. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
10. Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
11. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).
12. Active tuberculosis.
13. Active infection requiring systemic therapy.
14. Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines.
15. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3).
16. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behaviour; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Avelumab plus gemcitabine/carboplatin; 2 cycles of induction avelumab 10mg/kg every 2 weeks followed by 6 cycles of carboplatin/gemcitabine plus avelumab (carboplatin 5AUC day +1, gemcitabine 1000mg/m2 day +1 and +8 and avelumab 10mg/kg day +15) every 3 weeks followed by avelumab monotherapy 10mg/kg every 2 weeks until progressive disease or intolerance.	Combination product: avelumab 10mg/kg with carboplatin/gemcitabine; Dosage and schedule: Avelumab 10mg/kg will be administered over 60 minutes in the experimental arm as follows:Intravenously every 2 weeks for two cycles.During carboplatin-gemcitabine treatment, on day +15 (carboplatin will be administered on day 1; gemcitabine on days 1 and 8), for six cycles. Intravenously every 2 weeks until progressive disease o intolerance.Intravenously every 2 weeks until progressive disease or intolerance.; Carboplatin-gemcitabine will be administered for six cycles, every three weeks, with the following posology, according to the SmPCCarboplatin 5AUC day +1.Gemcitabine 1000mg/m2 day +1 and +8.; Other Names: Bavencio
Active Comparator: Gemcitabine/carboplatin alone; patients will receive 6 cycles of carboplatin/gemcitabine (carboplatin 5AUC day +1, gemcitabine 1000mg/m2 day +1 and +8) every 3 weeks.	Combination product: carboplatin/gemcitabine alone; •Carboplatin-gemcitabine will be administered for six cycles, every three weeks, with the following posology, according to the SmPC; Carboplatin 5AUC day +1.; Gemcitabine 1000mg/m2 day +1 and +8.; Other Names: Standard of care for UC treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	The ORR is defined as the sum of the complete and partial responses (CR+PR), (according to Response Evaluation Criteria in Solid Tumours [RECIST criteria v1.1] and iRECIST).	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Time from randomisation to either documented disease progression or death from any cause (whichever occurs earlier).	24 months
Overall Survival (OS)	Time from randomisation to death from any cause. Patients still alive at the time of OS analysis will be censored on their last date of contact. Patients who withdraw from the study without having completed the withdrawal consent will be followed up to determine their status whenever possible. For the purposes of this study, subjects should be evaluated every 6 weeks with the appropriate imaging technique according to each centre's routine practice, during the combined treatment, and every 9 weeks during the maintenance period. In case of cycle delay every 6 weeks should be maintained to avoid any bias in the assessment of the date of progression with the appropriate imaging studies for response evaluation. Response will be monitored as per the RECIST 1.1 criteria.	24 months
Duration of Response (DoR)	Time from the first confirmation of objective response according to RECIST 1.1 criteria until disease progression or death.	24 months
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	Incidence and severity of adverse events. AEs will be coded and evaluated using the National Cancer Institute, Common Toxicity criteria for Adverse Events (NCI-CTCAE) v4.03 toxicity criteria (if NCI-CTCAE are not applicable, the Medical Dictionary for Regulatory Activities [MedDRA] will be used).	24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of pathologic resistance mechanisms to treatment combination	Determination of resistance mechanisms in disease's biopsies, describing the pathologic features that may predict response or resistance to treatment.	24 months
Analysis of immunologic resistance mechanisms to treatment combination	Determination of resistance mechanisms in blood serum, describing the immunologic features that may predict response or resistance to treatment.	24 months
Analysis of genomic resistance mechanisms to treatment combination	Determination of PD-L1 expression in tumor infiltrating immune cells and in tumor cells (pre and post-treatment samples will be analyzed).	24 months

Collaborators and Investigators

• Sponsor: Associació per a la Recerca Oncologica, Spain
• Collaborators: Pivotal S.L.; Merck, S.L., Spain
• Investigators: Principal Investigator: Joaquín Bellmunt, MD, PhD, Hospital del Mar; Principal Investigator: Alejo Rodríguez-Vida, MD, PhD, Hospital del Mar

Publications and helpful links

General Publications

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• Witjes JA, Comperat E, Cowan NC, De Santis M, Gakis G, Lebret T, Ribal MJ, Van der Heijden AG, Sherif A; European Association of Urology. EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur Urol. 2014 Apr;65(4):778-92. doi: 10.1016/j.eururo.2013.11.046. Epub 2013 Dec 12.
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• http://www.mercknewsroom.com/news-release/oncology-newsroom/mercks-keynote-045-studying-keytruda-pembrolizumab-advanced-bladder-c.
• Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, Dawson NA, van der Heijden MS, Dreicer R, Srinivas S, Retz MM, Joseph RW, Drakaki A, Vaishampayan UN, Sridhar SS, Quinn DI, Duran I, Shaffer DR, Eigl BJ, Grivas PD, Yu EY, Li S, Kadel EE 3rd, Boyd Z, Bourgon R, Hegde PS, Mariathasan S, Thastrom A, Abidoye OO, Fine GD, Bajorin DF; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017 Jan 7;389(10064):67-76. doi: 10.1016/S0140-6736(16)32455-2. Epub 2016 Dec 8. Erratum In: Lancet. 2017 Aug 26;390(10097):848.
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• Rodriguez Vida A et al. Phase II randomized study of first line avelumab with carboplatin-gemcitabine versus carboplatin-gemcitabine alone in patients with metastatic urothelial carcinoma ineligible for cisplatin-based therapy. DOI: 10.1200/JCO.2018.36.15_suppl.TPS4591 Journal of Clinical Oncology 36, no. 15_suppl.
• Perez Valderrama B et al. LBA27 - Phase II multicenter, randomized study to evaluate efficacy and safety of avelumab with gemcitabine/carboplatin (CG) vs CG alone in patients with unresectable or metastatic urothelial carcinoma (mUC) who are ineligible to receive cisplatin-based therapy. Annals of Oncology (2020) 31 (suppl_4): S1142-S1215. 10.1016/annonc/annonc325.

Helpful Links

• APRO Website

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2018
• Primary Completion (Actual): August 31, 2022
• Study Completion (Actual): August 31, 2022

Study Registration Dates

• First Submitted: December 21, 2017
• First Submitted That Met QC Criteria: January 3, 2018
• First Posted (Actual): January 4, 2018

Study Record Updates

• Last Update Posted (Actual): October 18, 2023
• Last Update Submitted That Met QC Criteria: October 17, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Urothelial carcinoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Transitional Cell; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Carboplatin; Avelumab; Gemcitabine
• Other Study ID Numbers: MS100070_0160; 2017-004260-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No