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Avelumab Plus Carboplatin-gemcitabine in Urothelial Carcinoma (INDUCOMAIN)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03390595
Recruitment Status : Active, not recruiting
First Posted : January 4, 2018
Last Update Posted : April 30, 2021
Sponsor:
Collaborators:
Merck, S.L., Spain
Pivotal S.L.
Information provided by (Responsible Party):
Associació per a la Recerca Oncologica, Spain

Tracking Information
First Submitted Date  ICMJE December 21, 2017
First Posted Date  ICMJE January 4, 2018
Last Update Posted Date April 30, 2021
Actual Study Start Date  ICMJE May 17, 2018
Estimated Primary Completion Date August 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 12, 2018)		 Objective Response Rate (ORR) [ Time Frame: 24 months ]
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).
Original Primary Outcome Measures  ICMJE
 (submitted: January 3, 2018)		 Objective Response Rate (ORR) [ Time Frame: 24 months ]
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 irRECIST).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 3, 2018)
  • Progression-Free Survival (PFS) [ Time Frame: 24 months ]
    Time from randomisation to either documented disease progression or death from any cause (whichever occurs earlier).
  • Overall Survival (OS) [ Time Frame: 24 months ]
    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.
  • Duration of Response (DoR) [ Time Frame: 24 months ]
    Time from the first confirmation of objective response according to RECIST 1.1 criteria until disease progression or death.
  • Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 24 months ]
    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).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: January 3, 2018)
  • Analysis of pathologic resistance mechanisms to treatment combination [ Time Frame: 24 months ]
    Determination of resistance mechanisms in disease's biopsies, describing the pathologic features that may predict response or resistance to treatment.
  • Analysis of immunologic resistance mechanisms to treatment combination [ Time Frame: 24 months ]
    Determination of resistance mechanisms in blood serum, describing the immunologic features that may predict response or resistance to treatment.
  • Analysis of genomic resistance mechanisms to treatment combination [ Time Frame: 24 months ]
    Determination of PD-L1 expression in tumor infiltrating immune cells and in tumor cells (pre and post-treatment samples will be analyzed).
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Avelumab Plus Carboplatin-gemcitabine in Urothelial Carcinoma
Official Title  ICMJE 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.
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Urothelial Cancer
Intervention  ICMJE
  • 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 SmPC

      • Carboplatin 5AUC day +1.
      • Gemcitabine 1000mg/m2 day +1 and +8.
    Other Name: Bavencio
  • 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 Name: Standard of care for UC treatment
Study Arms  ICMJE
  • 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.
    Intervention: Combination Product: avelumab 10mg/kg with carboplatin/gemcitabine
  • 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.
    Intervention: Combination Product: carboplatin/gemcitabine alone
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 9, 2020)		 85
Original Estimated Enrollment  ICMJE
 (submitted: January 3, 2018)		 80
Estimated Study Completion Date  ICMJE August 2021
Estimated Primary Completion Date August 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03390595
Other Study ID Numbers  ICMJE MS100070_0160
2017-004260-36 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Associació per a la Recerca Oncologica, Spain
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Associació per a la Recerca Oncologica, Spain
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Merck, S.L., Spain
  • Pivotal S.L.
Investigators  ICMJE
Principal Investigator: Joaquín Bellmunt, MD, PhD Hospital del Mar
Principal Investigator: Alejo Rodríguez-Vida, MD, PhD Hospital del Mar
PRS Account Associació per a la Recerca Oncologica, Spain
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP