| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Urothelial Carcinoma |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064467 |
| E.1.2 | Term | Urothelial carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1(1) in patients with baseline mMDSC levels ≥22.3% following combination treatment with nivolumab plus IPI-549 with that of nivolumab monotherapy. |
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| E.2.2 | Secondary objectives of the trial |
•To compare ORR per RECIST v1.1 in patients with baseline mMDSC levels <22.3% and in all patients regardless of baseline mMDSC level following combination treatment with nivolumab plus IPI-549 with that of nivolumab monotherapy.
•To evaluate time to response (TTR), duration of response (DOR), and progression-free survival (PFS) following combination treatment with nivolumab plus IPI-549 relative to nivolumab monotherapy.
•To evaluate the safety of combination treatment with nivolumab plus IPI-549.
•To evaluate the pharmacokinetics (PK) of IPI-549 administered in combination with nivolumab.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.≥18 years of age.
2.Have signed and dated an independent review board (IRB)/independent ethics committee (IEC) approved informed consent form (ICF) in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal patient care.
3.Willing and able to comply with scheduled visits, treatment schedule, laboratory tests, fresh tumor biopsies, and all other protocol requirements.
4.Patients with histologically or cytologically confirmed urothelial carcinoma (including mixed histologies of urothelial carcinoma with elements of other subtypes) of the renal pelvis, ureter, bladder, or urethra, who meet one of the following:
a.Have progression or refractory disease. Patients must have had at least 1 platinum-based chemotherapy regimen for the treatment of metastatic (Stage IV) or locally advanced unresectable disease; or
b.Have disease recurrence within 1 year of completing a platinum-based neoadjuvant or adjuvant therapy; or
5.At least 1 measurable disease lesion by computed tomography (CT) or magnetic resonance imaging (MRI) as defined by RECIST v1.1 performed within 1 month prior to first dose.
6.Willing to undergo one pre-treatment core biopsy (unless archival tumor tissue is available within 3 months of first dose) and one on-treatment tumor biopsy with an additional (optional) post-treatment tumor biopsy for an exploratory analysis of mechanisms of resistance. Biopsies performed during the study may be omitted under certain circumstances; for example, if considered medically unfeasible after a discussion between the Investigator and Medical Monitor.
Baseline tumor biopsies should preferably be performed from a tumor site that is NOT the only site of measurable disease. For patients with only one site of measurable disease, tumor biopsies are allowed if at least one of the following criteria is met:
a.CT imaging performed after biopsy and there is still measurable disease, or
b.The type of biopsy is not expected to impact the measurability (eg, core needle biopsy) regardless of when imaging occurred, prior to or after biopsy.
Tumor material from core biopsies done before the screening period is acceptable if the biopsy was performed within 3 months prior to the planned treatment start and no new systemic cancer therapy was administered after the biopsy and before study entry.
7.Tumor tissue (archived [without time constraints] or new biopsy) should be provided for biomarker analysis, including PD-L1 expression level per central laboratory (Dako PD-L1 immunohistochemical 28-8 pharmDx kit).
8.Blood sample must be provided to the central laboratory for evaluation of mMDSC levels, as measured by Clinical Laboratory Improvement Amendments (CLIA)-certified Serametrix flow cytometry assay. Patients must have a confirmed result of mMDSC level for randomization into the study.
9.Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
10.Baseline laboratory values must meet the following criteria within 14 days of the first dose:
a.Adequate hematologic function, defined as white blood cell (WBC) count ≥2.0 × 109/L, absolute neutrophil count ≥1.5 × 109/L, hemoglobin ≥9.0 g/dL, and platelet count ≥100 × 109/L.
b.Creatinine clearance ≥30 mL/min, as determined by either of the following:
Estimation as calculated by Cockcroft-Gault equation;
Direct measurement by 24-hour urine collection.
c.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 × upper limit of normal (ULN) (<5 × ULN if liver metastasis).
d.Total bilirubin ≤1.5 × ULN (unless elevated due to Gilbert’s syndrome who can have total bilirubin <3.0 mg/dL).
e.Albumin ≥3 g/dL.
11.Patients who have received more than 2 prior lines of chemotherapy must not have liver metastases. Sequential chemotherapy given as a planned sequence to optimize response will count as 1 regimen.
12.Prior focal radiotherapy to an isolated bony or soft tissue metastasis should be completed at least 2 weeks before study drug administration.
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| E.4 | Principal exclusion criteria |
Patients are to be excluded from the study if they meet any of the following criteria:
1.Active brain metastases or leptomeningeal metastases. Patients with brain metastases are eligible if these have been treated and there is no MRI evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. Patients with incidental findings of asymptomatic brain metastases at screening may start study treatment without prior radiation treatment after discussion between the Infinity Medical Monitor or designee and Investigator.
2.Any serious or uncontrolled medical disorder that, in the opinion of the Investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the patient to receive protocol therapy, or interfere with the interpretation of study results.
3.Other prior malignancy active within the previous 3 years except for local or organ confined early stage cancer that has been definitively treated with curative intent, does not require ongoing treatment, has no evidence of residual active disease, and has a negligible risk of recurrence and is therefore unlikely to interfere with the primary and secondary endpoints of the study, including response rate and safety.
4.Active, known, or suspected autoimmune disease. Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
5.Condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first dose. Inhaled or topical steroids, and adrenal replacement steroid doses are permitted in the absence of active autoimmune disease.
6.Prior therapy with experimental anti-tumor vaccines; any T cell co-stimulation or checkpoint pathways, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, including ipilimumab, or other medicines specifically targeting the T cell; or IPI-549.
7.Treatment with any chemotherapy, radiation therapy, biologics for cancer, or investigational therapy within 28 days of first administration of study treatment (patients with prior cytotoxic or investigational products <28 days prior to treatment might be eligible after discussion between Investigator and Infinity Medical Monitor or designee, if toxicities from the prior treatment have resolved to CTCAE Grade 1 level).
8.Treatment with botanical preparations (eg, herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to randomization.
9.Major surgery within 4 weeks prior to Screening.
10.Positive test for hepatitis B virus (HBV) using hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) or positive test for hepatitis C virus (HCV) using HCV RNA test indicating acute or chronic infection.
11.Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
12.Dependence on continuous supplemental oxygen use.
13.History of allergy to study drug components or severe hypersensitivity reaction to any monoclonal antibody.
14.Ongoing systemic bacterial, fungal, or viral infections at Screening.
NOTE: Patients on antimicrobial, antifungal, or antiviral prophylaxis are not specifically excluded if all other inclusion/exclusion criteria are met.
15.Administration of a live or attenuated vaccine within 6 weeks of first dose of study drug.
16.Administration of any of the following within 1 week prior to the administration of study drug:
a. Strong inhibitors or inducers of cytochrome P450 (CYP) 3A4 and 2C8, including grapefruit, grapefruit juice and herbal supplements
b.Warfarin, phenytoin, or other substrates of CYP2C8 or CYP2C9 with a narrow therapeutic range.
c.P-glycoprotein (P-gp) inhibitors;
17.Baseline QT interval corrected with Fridericia’s method (QTcF) > 480 ms.
NOTE: criterion does not apply to patients with a right or left bundle branch block.
18.Prior surgery or gastrointestinal dysfunction that may affect drug absorption (eg gastric bypass surgery, gastrectomy).
19.WOCBP who are pregnant or breastfeeding.
20.Women with a positive pregnancy test at enrollment or prior to administration of study medication.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint for this study is ORR, with objective response defined as best response of complete response or partial response as measured by RECIST v1.1 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Response to treatment will be determined based on radiographic evaluations and assessments conducted by the Investigators using RECIST v1.1 at baseline, every 8 weeks through Week 48 and at least every 12 weeks thereafter until disease progression. |
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| E.5.2 | Secondary end point(s) |
The secondary endpoints for this study are:
•TTR, defined as the time from the first dose of study treatment to first objective response (CR or PR) in patients with CR or PR.
•DOR, defined as the time from the first objective response (CR or PR) to documented disease progression in patients with CR or PR.
•PFS, defined as the time from the first dose of study treatment to documented disease progression or death due to any cause.
•Incidence of TEAEs, immune-mediated AEs (IMAEs), SAEs, including deaths, AEs leading to treatment discontinuation, changes from baseline in safety laboratory parameters, vital signs, and electrocardiograms (ECGs).
•Population PK estimates, including inter- and intra-subject variability, covariate effects and drug-interaction parameters.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
During the treatment period, patients will be evaluated for safety based on monitoring for adverse events (AEs) and concomitant medications, and physical examinations, vital signs, ECGs, clinical laboratory tests (hematology, chemistry, urinalysis), and Eastern Cooperative Oncology (ECOG) performance status. Blood samples for population PK assessment will be obtained on Day 1 of Cycles 1 and 2 through 6 hours following administration of IPI-549 (or placebo).
The date of progression to be used for all relevant time-to-event endpoints will be based on first documentation of PD (ie, RECIST v1.1 date of PD), regardless of date of confirmation of PD for patients who continue on treatment.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Czech Republic |
| France |
| Georgia |
| Germany |
| Italy |
| Poland |
| Serbia |
| Spain |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the study will occur 2 years after the enrollment of the last patient to account for survival follow-up of all patients. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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