An Study to Evaluate the Safety and Efficacy of Copanlisib in Combination With Nivolumab in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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The purpose of the dose escalation part of this study is to determine the feasibility of using the combination of copanlisib and nivolumab in subjects with advanced solid tumors, and to determine the maximum tolerated dose of copanlisib in combination with nivolumab. The maximum tolerated dose will then be used in Phase 2 (dose expansion) of the study.

Detailed Description
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Study was originally designed with both Phase I and Phase II part, but sponsor decided not to conduct Phase 2 part due to strategic portfolio re-prioritization.

Official Title
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An Open-label, Multi-center, Phase 1b/2 Study to Evaluate the Safety and Efficacy of Copanlisib in Combination With Nivolumab in Patients With Advanced Solid Tumors.

Conditions
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Non-small Cell Lung Cancer (NSCLC), Head and Neck Squamous Cell Carcinoma (HNSCC), Hepatocellular Carcinoma (HCC)

Intervention / Treatment
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* Drug: Copanlisib
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with a histologically confirmed diagnosis of: Phase 1b: Advanced solid tumors where nivolumab is indicated as per the latest nivolumab Prescribing Information, Phase 2: Metastatic NSCLC, progressing on or after prior pembrolizumab therapy with or without chemotherapy, irrespective of PD-L1 expression Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations. Recurrent or metastatic HNSCC progressing on or after prior pembrolizumab therapy with or without chemotherapy HCC progressing after any prior therapy. Exclusion Criteria: Active, known or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Major surgery, open biopsy or significant traumatic injury ≤ 28 days prior to first administration of study intervention. Central line surgery is not considered major surgery Symptomatic metastatic brain or meningeal carcinomatosis or tumors unless the participant is > 6 months from definitive therapy (surgery or radiotherapy), has no evidence of tumor growth on an imaging study and is clinically stable with respect to the tumor at the start of study intervention. Other malignancy within the last 5 years except for the following, which are permitted: curatively treated basal cell/squamous cell skin cancer, carcinoma in situ of the cervix, superficial transitional cell bladder carcinoma (if BCG [Bacillus Calmette-Guerin] treatment was given, there should be a minimum of 6 months between last dose and enrollment), in situ ductal carcinoma of the breast after complete resection, participants with localized, resected and/or low-risk prostate cancer may be eligible after discussion with the sponsor's designated medical representative and sponsor's approval. Other protocol inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation<br>Copanlisib: 45 mg (dose level -1) or 60 mg (dose level 1) on Day 1, Day 8 and Day 15 (28 day cycle) Nivolumab: 240 mg on Day 15 of Cycle 1 and on Day 1 and Day 15 of subsequent cycles (28 day cycle). | Drug: Copanlisib<br>* Copanlisib: lyophilisate for reconstitution and further dilution for infusion<br>Drug: Nivolumab<br>* Nivolumab: concentrate for solution for infusion<br>|
| Experimental: Dose expansion<br>Copanlisib: Recommended phase 2 dose established in the phase 1b part on Day 1, Day 8 and Day 15 (28 day cycle) Nivolumab: 240 mg on Day 15 of Cycle 1 and on Day 1 and Day 15 of subsequent cycles (28 day cycle). | Drug: Copanlisib<br>* Copanlisib: lyophilisate for reconstitution and further dilution for infusion<br>Drug: Nivolumab<br>* Nivolumab: concentrate for solution for infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Frequency of dose limiting toxicities (DLT) at each dose level associated with administration of copanlisib and nivolumab |  | At the end of Cycle 2 of a 28-day cycle | 
| Phase 2: Overall response rate (ORR) as per RECIST v 1.1 (Response evaluation criteria in solid tumors, v 1.1) (by local investigator |  | Up to 26 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Overall response rate (ORR) as per RECIST v 1.1 (by local investigator assessment) |  | Up to 26 months | 
| Phase 1b and 2:Maximum drug concentration in plasma (Cmax) of copanlisib |  | At cycle1 day15, cycle2 day15, cycle 6 day15 | 
| Phase 1b and 2:Area under the curve (AUC) of copanlisib |  | At cycle1 day15, cycle2 day15,cycle 6 day15 | 
| Phase 1b and 2: Cmax for nivolumab |  | At cycle1 day15, cycle2 day15,cycle 6 day15 | 
| Phase 1b and 2: Minimum plasma drug concentration (Cmin) for nivolumab |  | At cycle1 day15, cycle2 day15,cycle 6 day15 | 
| Phase 1b and 2: Overall survival (OS) |  | Up to 26 months | 
| Phase 1b and 2: Progression-free survival (PFS) |  | Up to 26 months | 
| Phase 1b and 2: Disease control rate (DCR) |  | Up to 26 months | 
| Phase 1b and 2: Duration of stable disease (DSD) |  | Up to 26 months | 
| Phase 1b and 2: Time to response (TTR) |  | Up to 26 months | 
| Phase 1b and 2: Time to progression (TTP) |  | Up to 26 months | 
| Phase 1b and 2: Duration of response (DOR) |  | Up to 26 months | 
| Phase 1b and 2:Number of participants with Adverse events (AE) and Serious AEs (SAE) |  | Up to 26 months | 
| Phase 1b and 2:Number of participants with clinically significantly abnormal changes in electrocardiograms (ECG) including heart rate and measures PR, QRS, QT, and QTc intervals |  | Up to 26 months | 
| Phase 1b and 2:Number of participants with changes in dose including interruptions, reductions and dose intensity |  | Up to 26 months |