Staggered, Chemo-Immunotherapy With Durvalumab, MEDI4736 Pemetrexed & Carboplatin (PC) for Metastatic Non-Squamous NSCLC

Study Overview
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Brief Summary
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This is a Phase II, open label, randomized study of durvalumab in combination with pemetrexed and carboplatin in eligible adult patients with locally advanced or metastatic non-small cell lung cancer. The study will focus on the efficacy of two alternative staggered dosing regimens.

Detailed Description
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This trial will evaluated two different schedules of concurrent chemoimmunotherapy while simultaneously measuring immune activation, immune resistance and host factors. Both arms will consist of concurrent chemoimmunotherapy with durvalumab, pemetrexed and carboplatin, but in arm 1 the chemotherapy will precede the immunotherapy by a week and in arm 2 the immunotherapy will precede the chemotherapy by a week. Staggering these therapies still allows concurrent administration while allowing some degree of temporal isolation to better understand the contributions by chemotherapy and immunotherapy in this setting. Host and laboratory factors will be measured during treatment. We hypothesize that staggered dosing of immunotherapy in combination with chemotherapy can improve clinical benefit.

Official Title
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A Randomized, Phase II Study of Staggered, Chemo-Immunotherapy With Durvalumab, MEDI4736 Pemetrexed and Carboplatin (PC) for Metastatic Non-Squamous NSCLC

Conditions
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Non-Small Cell Lung Cancer Metastatic

Intervention / Treatment
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* Drug: Durvalumab
* Drug: Pemetrexed
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subject aged ≥ 18 years. Histologically or cytologically confirmed metastatic non-squamous non-small cell lung cancer. Patient has measurable disease as defined by RECIST 1.1 as assessed by either CT or MRI. Chemoimmunotherapy naïve (including durvalumab). ECOG Performance Status ≤ 2. --Note: If performance status = 2, ensure that there is a slot available prior to registration as only 20 PS = 2 patients will be enrolled on the protocol. Must have a life expectancy of at least 12 weeks. Adequate organ function as defined as: Hematologic: White blood cell count > 2.0 g/dL Platelet count ≥ 100,000/mm3 Hemoglobin ≥ 9 g/dL Absolute neutrophil count (ANC) ≥ 1,500/mm3 Hepatic: Total Bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) Except for patients with Gilbert's syndrome. AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN or ≤ 5 × institutional ULN if liver metastases are present Renal: eGFR ≥ 30 mL/min/1.73m2 or creatinine clearance ≥ 30 mL/min by Cockcroft-Gault: Males: ((140-age)×weight[kg])/(serum creatinine [mg/dL]×72) Females: (((140-age)×weight[kg])/(serum creatinine [mg/dL]×72))×0.85 Concurrent enrollment in the study, Rethinking Measurement of Performance Status in Cancer Patients, IRB 112529. Concurrent enrollment in the study, An Observational Study Assessing the Clinical Effectiveness of the VeriStrat® Test and Validating Immunotherapy Tests in Subjects with Non-Small Cell Lung Cancer, IRB 100314. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). Highly effective contraception for both male and female subjects throughout the study and for at least 3 months after the last dose of study therapy. Recovery to baseline or ≤ Grade 1 CTCAE v.5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. Exclusion Criteria: ALK or EGFR non-squamous non-small cell lung cancer. Prior radiation therapy within 2 weeks prior to cycle one day one. -Exception: Prior palliative radiotherapy is permitted, provided it has been completed at least 2 days prior to study enrollment and no clinically significant toxicities are expected. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. -Note: Local surgery of isolated lesions for palliative intent is acceptable. History of allogenic organ transplantation. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: Patients with vitiligo or alopecia Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement Any chronic skin condition that does not require systemic therapy Patients without active disease in the last 5 years may be included but only after consultation with the principal investigator Patients with celiac disease controlled by diet alone Current or prior use of immunosuppressive medication within 14 days of cycle one day one, EXCEPT for the following permitted steroids: --Intranasal, inhaled, topical steroids, eye drops or local steroid injection (eg,intra-articular injection); Systemic corticosteroids at physiologic doses ≤ 10mg/day of prednisone or equivalent; Steroids as premedication for hypersensitivity reactions (eg, computed tomography (CT) scan premedication). History of active primary immunodeficiency Diagnosis of any other malignancy within 2 years prior to study enrollment, except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the breast, bladder or of the cervix, and low-grade (Gleason 6 or below) prostate cancer on surveillance with no plans for treatment intervention (eg, surgery, radiation, or castration) or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms is allowed. Uncontrolled CNS metastases; subjects with previously treated brain metastases will be allowed if the brain metastases have been treated, toxicities have resolved to grade 1 or baseline and steroids are no longer required. --Patients with asymptomatic brain metastasis are allowed if previous steroid treatment was discontinued ≥ 6 weeks. History of leptomeningeal carcinomatosis Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent Known HIV infection with a detectable viral load within 6 months of the anticipated start of treatment. -Note: Patients on effective anti-retroviral therapy with an undetectable viral load within 6 months of the anticipated start of treatment are eligible for this trial. Active infection including: tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C. -Note: Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Vaccination with a live vaccine within 30 days of cycle one day one and while on trial is prohibited except for administration of inactivated vaccines. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies, cisplatin, other platinum-containing compounds, or mannitol. (NCI CTCAE v5.0 Grade ≥ 3). Subjects taking prohibited medications as described in Section 6.5.2. A washout period of prohibited medications for a period of at least 5 half-lives or as clinically indicated should occur prior to the start of treatment.

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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase II, open label, randomized study of durvalumab in combination with pemetrexed and carboplatin in eligible adult patients with locally advanced or metastatic non-small cell lung cancer.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm B: Immuno-Chemo<br>ArmB receives immunotherapy on D1 and chemotherapy on D8 of a 28-day cycle for the first 2cycles. After the first 2cycles, patients on Arm A and Arm B will be administered chemotherapy and immunotherapy on D1 of a 21day cycle for cycles 3 and 4. After 4cycles of chemo-immunotherapy, patients receive maintenance therapy with durvalumab and pemetrexed until treatment discontinuation. Maintenance therapy is administered on D1 of a 21day cycle. | Drug: Durvalumab<br>* Durvalumab is administered at a dose of 1500mg for patients who weigh >30 kg. If weight falls to ≤ 30 kg, weight-based dosing at 20mg/kg will be a utilized<br>* Other names: Imfinzi;Drug: Pemetrexed<br>* Pemetrexed dosing is adjusted for kidney function. Pemetrexed is dosed at 500mg/m2 for patients with a creatinine clearance ≥ 45 mL/min (by Cockcroft-Gault formula). If creatinine clearance is < 45 mL/min, pemetrexed is dosed at 400 mg/m2.<br>* Other names: Alimta;Drug: Carboplatin<br>* Carboplatin dosing is adjusted for kidney function.The total dose (in mg) of carboplatin will be calculated using the Calvert Formula utilizing a target AUC of 5 and a patient's GFR in mL/min.<br>|
| Experimental: Arm A: Chemo-Immuno<br>ArmA receives chemotherapy on D1 and immunotherapy on D8 of a 28-day cycle for the first 2cycles. After the first 2cycles, patients on Arm A and Arm B will be administered chemotherapy and immunotherapy on D1 of a 21day cycle for cycles 3 and 4. After 4cycles of chemo-immunotherapy, patients receive maintenance therapy with durvalumab and pemetrexed until treatment discontinuation. Maintenance therapy is administered on D1 of a 21day cycle. | Drug: Durvalumab<br>* Durvalumab is administered at a dose of 1500mg for patients who weigh >30 kg. If weight falls to ≤ 30 kg, weight-based dosing at 20mg/kg will be a utilized<br>* Other names: Imfinzi;Drug: Pemetrexed<br>* Pemetrexed dosing is adjusted for kidney function. Pemetrexed is dosed at 500mg/m2 for patients with a creatinine clearance ≥ 45 mL/min (by Cockcroft-Gault formula). If creatinine clearance is < 45 mL/min, pemetrexed is dosed at 400 mg/m2.<br>* Other names: Alimta;Drug: Carboplatin<br>* Carboplatin dosing is adjusted for kidney function.The total dose (in mg) of carboplatin will be calculated using the Calvert Formula utilizing a target AUC of 5 and a patient's GFR in mL/min.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of clinical benefit | Described using RECIST 1.1 response criteria. | up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Adverse events (AEs) and serious adverse events (SAEs) will be collected and assessed by CTCAE, v5.0 for assessment of safety and feasibility. | up to 5 years | 
| Objective response rate (ORR) | Assessed using RECIST 1.1 | up to 5 years | 
| Progression free survival (PFS) | Assessed as the time between trial initiation and documented progression or radiographic imaging. | up to 5 years | 
| Overall survival (OS) | assessed as the time from trial initiation until death from any cause. | up to 5 years |