Immunotherapy in Combination With Chemoradiation in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This is an open-label, multicenter, phase I study to evaluate the safety and tolerability of durvalumab ± tremelimumab in combination with chemoradiation in patients with advanced solid tumors

Detailed Description
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This study will initially treat up to approximately 300 patients with advanced solid tumors at approximately 30 sites, worldwide. The study will be composed of a dose-limiting toxicity (DLT) assessment phase (Part A) and an expansion phase (Part B).

Official Title
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A Phase I Multicenter Study of Immunotherapy in Combination With Chemoradiation in Patients With Advanced Solid Tumors (CLOVER)

Conditions
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Carcinoma, Squamous Cell of Head and Neck, Carcinoma, Non-Small-Cell Lung, Small Cell Lung Carcinoma

Intervention / Treatment
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* Drug: Durvalumab
* Drug: Tremelimumab
* Drug: Cisplatin (dose level 4)
* Drug: Cisplatin (dose level 3)
* Drug: Carboplatin (dose level 1)
* Drug: Carboplatin (dose level 2)
* Drug: Etoposide (dose level 1)
* Drug: Etoposide (dose level 2)
* Drug: Paclitaxel
* Drug: Pemetrexed
* Radiation: External beam radiation (dose level 1)
* Radiation: External beam radiation (dose level 2)
* Radiation: External beam radiation (hyperfractionated)
* Drug: Cisplatin (dose level 1)
* Drug: Cisplatin (dose level 2)
* Radiation: External beam radiation (standard)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: World Health Organization (WHO)/ECOG performance status of 0 or 1 Body weight >30 kg at enrollment and treatment assignment At least 1 measurable lesion, not previously irradiated No prior exposure to immune-mediated therapy (including therapeutic anticancer vaccines) For patients with oropharyngeal HNSCC HPV status has to be known Exclusion criteria: Patients with simultaneous primary malignancies or bilateral tumors Active or prior documented autoimmune or inflammatory disorders Brain metastases or spinal cord compression Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV; positive HIV 1/2 antibodies) Has a paraneoplastic syndrome (PNS) of autoimmune nature HNSCC cohort: Head and neck cancer that does not include unresectable, locally advanced cancer of oral cavity, larynx, oropharynx or hypopharynx. HNSCC of unknown primary are also excluded NSCLC and SCLC cohort: Mixed SCLC and NSCLC histology SCLC cohort: Extensive-stage SCLC

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 110 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HNSCC Arm 1<br>Durvalumab + cisplatin with radiation in patients with locally advanced squamous cell carcinoma of the head and neck (HNSCC) | Drug: Durvalumab<br>* IV (intravenous)<br>* Other names: MEDI4736;Drug: Cisplatin (dose level 4)<br>* IV<br>Radiation: External beam radiation (dose level 1)<br>* radiation therapy<br>|
| Experimental: NSCLC Arm 1<br>Durvalumab + cisplatin and etoposide with radiation in patients with locally advanced, unresectable (Stage III) non-small-cell lung cancer (NSCLC) | Drug: Durvalumab<br>* IV (intravenous)<br>* Other names: MEDI4736;Drug: Etoposide (dose level 1)<br>* IV<br>Radiation: External beam radiation (dose level 2)<br>* radiation therapy<br>Drug: Cisplatin (dose level 1)<br>* IV<br>|
| Experimental: NSCLC Arm 2<br>Durvalumab + carboplatin and paclitaxel with radiation in patients with locally advanced, unresectable (Stage III) non-small-cell lung cancer (NSCLC) | Drug: Durvalumab<br>* IV (intravenous)<br>* Other names: MEDI4736;Drug: Carboplatin (dose level 1)<br>* IV<br>Drug: Paclitaxel<br>* IV<br>Radiation: External beam radiation (dose level 2)<br>* radiation therapy<br>|
| Experimental: NSCLC Arm 3<br>Investigator's choice of carboplatin and pemetrexed OR cisplatin and pemetrexed | Drug: Durvalumab<br>* IV (intravenous)<br>* Other names: MEDI4736;Drug: Carboplatin (dose level 2)<br>* IV<br>Drug: Pemetrexed<br>* IV<br>Radiation: External beam radiation (dose level 2)<br>* radiation therapy<br>Drug: Cisplatin (dose level 2)<br>* IV<br>|
| Experimental: SCLC Arm 1<br>Patients should start with cisplatin, but if cisplatin is not tolerated, they have the option to switch to carboplatin | Drug: Durvalumab<br>* IV (intravenous)<br>* Other names: MEDI4736;Drug: Cisplatin (dose level 3)<br>* IV<br>Drug: Carboplatin (dose level 2)<br>* IV<br>Drug: Etoposide (dose level 2)<br>* IV<br>Radiation: External beam radiation (standard)<br>* radiation therapy<br>|
| Experimental: SCLC Arm 2<br>Patients with limited-stage small-cell lung cancer (SCLC) should start with cisplatin, but if cisplatin is not tolerated, they have the option to switch to carboplatin | Drug: Durvalumab<br>* IV (intravenous)<br>* Other names: MEDI4736;Drug: Cisplatin (dose level 3)<br>* IV<br>Drug: Carboplatin (dose level 2)<br>* IV<br>Drug: Etoposide (dose level 2)<br>* IV<br>Radiation: External beam radiation (hyperfractionated)<br>* radiation therapy<br>|
| Experimental: SCLC Arm 3<br>Patients should start with cisplatin, but if cisplatin is not tolerated, they have the option to switch to carboplatin. Note: Arm 3 will only be opened if the regimen in SCLC Arm 1 is safe and tolerable. | Drug: Durvalumab<br>* IV (intravenous)<br>* Other names: MEDI4736;Drug: Tremelimumab<br>* IV<br>Drug: Cisplatin (dose level 3)<br>* IV<br>Drug: Carboplatin (dose level 2)<br>* IV<br>Drug: Etoposide (dose level 2)<br>* IV<br>Radiation: External beam radiation (standard)<br>* radiation therapy<br>|
| Experimental: SCLC Arm 4<br>Patients should start with cisplatin, but if cisplatin is not tolerated, they have the option to switch to carboplatin Note: Arm 4 will only be opened if the regimen in SCLC Arm 2 is safe and tolerable. | Drug: Durvalumab<br>* IV (intravenous)<br>* Other names: MEDI4736;Drug: Tremelimumab<br>* IV<br>Drug: Cisplatin (dose level 3)<br>* IV<br>Drug: Carboplatin (dose level 2)<br>* IV<br>Drug: Etoposide (dose level 2)<br>* IV<br>Radiation: External beam radiation (hyperfractionated)<br>* radiation therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with Dose Limiting Toxicities (DLTs) |  | From first dose of durvalumab until 28 days after completion of radiation therapy | 
| Number of subjects with Adverse Events (AEs) |  | From first dose of durvalumab up to 90 days after the last dose of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) |  | From first dose until the date of objective disease progression or death, in the absence of progression at 12, 18 and 24 months, up to 4 years. | 
| Overall Survival (OS) |  | From first dose until death due to any cause through study completion, up to 4 years | 
| Objective response rate (ORR) | Number (%) of patients with an overall response of complete response (CR) or partial response (PR). | From first dose until disease progression, or the last evaluable assessment in the absence of progression, assessed up to 4 years. | 
| Best objective response (BoR) | The best response based on the overall visit responses from each RECIST 1.1 assessment or the last evaluable assessment in the absence of RECIST 1.1 progression. | From first dose until disease progression, or the last evaluable assessment in the absence of progression, assessed up to 4 years. | 
| Duration of response (DoR) | Time from the date of first documented response until the first date of documented progression or death in the absence of disease progression. | From first dose until disease progression, or death, in the absence of progression, assessed up to 4 years. | 
| Disease control rate (DCR) |  | From first dose until disease progression, at 18 weeks and 48 weeks. | 
| Disease-free survival (DFS) |  | From first dose until disease progression or death, in the absence of progression at 12, 18 and 24 months, assessed up to 4 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Durvalumab, Chemotherapy, Radiotherapy, HNSCC, NSCLC, SCLC, locally-advanced, limited stage, first line