QUILT-3.055: a Study of Combination Immunotherapies in Patients Who Have Previously Received Treatment with Immune Checkpoint Inhibitors

ImmunityBio

Status and phase: Enrolling; Phase 2

Conditions: Microsatellite Instability; Melanoma; Small Cell Lung Cancer; Urothelial Carcinoma; Merkel Cell Carcinoma; Non-Small Cell Lung Cancer; Mismatch Repair Deficiency; Gastric Cancer; Hepatocellular Carcinoma; Renal Cell Carcinoma; Cervical Cancer; Colorectal Cancer; Head and Neck Squamous Cell Carcinoma

Treatments: Drug: N-803 + Atezolizumab + PD-L1 t-haNK; Drug: N-803 + Pembrolizumab; Drug: N-803 + Pembrolizumab + PD-L1 t-haNK; Drug: N-803 + Atezolizumab; Drug: N-803 + Docetaxel + Pembrolizumab; Drug: N-803 + Nivolumab; Drug: N-803 + Durvalumab + PD-L1 t-haNK; Drug: N-803 + Nivolumab + PD-L1 t-haNK; Drug: N-803 + Docetaxel + Nivolumab; Drug: N-803 + Avelumab; Drug: N-803 + Avelumab + PD-L1 t-haNK; Drug: N-803 + Durvalumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT03228667

CA-ALT-803-02-17

Details and patient eligibility

About

This Phase 2b, multicohort, open-label clinical trial (QUILT-3.055) evaluates combination immunotherapies in patients with various advanced solid tumors who have progressed following prior PD-1/PD-L1 checkpoint inhibitor therapy. The trial includes six cohorts:

Cohorts 1-4: Patients who progressed after an initial response (PR or CR) to prior PD-1/PD-L1 therapy, receiving combination therapy with N-803 and a PD-1/PD-L1 checkpoint inhibitor. (Closed to enrollment)

Cohort 5: Patients who progressed while receiving treatment in cohorts 1-4; they receive combination therapy with N-803, a PD-1/PD-L1 checkpoint inhibitor, and PD-L1 t-haNK cells.(Closed to enrollment)

Cohort 6A & 6B: Patients with acquired resistance to prior PD-1/PD-L1 therapy; they receive combination therapy with N-803, docetaxel, and either pembrolizumab (6A) or nivolumab (6B).

Treatment is administered for up to two years or until disease progression, and participants are closely monitored for adverse events (AEs), including immune-related AEs, with specific dose modifications outlined. The primary endpoint is objective response rate (ORR) assessed by RECIST v1.1. The study uses Simon's two-stage design for cohorts 1-3 to determine the optimal dose and further assesses safety and efficacy endpoints for all cohorts.

Full description

Conly Cohort 6 is recruiting.

Enrollment: 40 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

INCLUSION CRITERIA (Cohort 6 only)

1. Age ≥ 18 years old.

2. Able to understand and provide a signed informed consent that fulfills the relevant IRB/IEC guidelines.

3. Pathologically confirmed stage IV NSCLC disease.

4. Have received exactly 1 anti-PD-1 or anti-PD-L1 therapy (either pembrolizumab or nivolumab) for advanced disease (stage IV or recurrent disease, or stage I-III disease in certain circumstances) outlined below. Anti-PD-1 or anti-PD-L1 therapy may have been given alone or in combination with other therapy.

   a. For those participants who received neoadjuvant, adjuvant, and/or consolidation anti-PD-1 or anti-PD-L1 therapy for stage

   I-III disease:

   If they had disease progression within (≤) 365 days from initiation (cycle 1 day 1) of anti-PD-1 or anti-PD-L1 therapy, this counts as the single allowed anti-PD-1 or anti-PD-L1 therapy for advanced disease OR if they had disease progression more than (>) 365 days from initiation (cycle 1 day 1) of anti-PD-1 or anti-PD-L1 therapy, this is not considered anti-PD-1 or anti-PD-L1 therapy for advanced disease. These participants must have received anti-PD-1 or anti-PD-L1 therapy for stage IV or recurrent disease.

5. Have reported disease progression (in the opinion of the treating physician) more than (>) 84 days following initiation (cycle 1 day 1) of their most recent anti-PD-1 or anti-PD-L1 therapy (either pembrolizumab or nivolumab).

6. Participants who received anti-PD-1 or anti-PD-L1 therapy for stage IV or recurrent disease, must have had a best response of SD, PR or CR (in the opinion of the treating physician) on the anti- PD-1 or anti-PD-L1 therapy (either nivolumab or pembrolizumab) for stage IV or recurrent disease.

7. Participants with a known sensitizing mutation for which an - approved targeted therapy for NSCLC exists (e.g., EGFR, ALK, ROS1, BRAF, RET, NTRK, KRAS, HER2 and MET sensitizing mutations), must have previously received at least 1 of the approved therapy(s). Prior targeted therapy for participants with targetable alterations is allowed if all other eligibility criteria are also met.

8. ECOG performance status of 0 to 2.

9. Measurable tumor lesions according to RECIST v1.1.

10. Ability to attend required study visits and return for adequate follow-up, as required by this protocol.

11. Agreement to practice effective contraception for female participants of child-bearing potential and non-sterile males. Female participants of child-bearing potential must agree to use effective contraception for up 7 months after completion of therapy, and non-sterile male participants must agree to use a condom for up to 7 months after treatment. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), orals, injectables, 2 forms of barrier methods (eg, condom, diaphragm) used with spermicide, intrauterine devices (IUDs), and hormonal therapy.

EXCLUSION CRITERIA (Cohort 6 only)

1. Systemic autoimmune disease currently requiring treatment (e.g., lupus erythematosus, rheumatoid arthritis, Addison's disease, or autoimmune disease associated with lymphoma). The participant must have been off treatment for 180 days.

2. History of organ transplant requiring immunosuppression; or history of pneumonitis or interstitial lung disease requiring treatment with systemic steroids; or a history of receiving systemic steroid therapy or any other immunosuppressive medication ≤ 3 days prior to study initiation. Daily steroid replacement therapy (eg, prednisone or hydrocortisone) and corticosteroids used to manage AEs are permitted.

3. History of known active hepatitis B or C infection.

4. Active infection requiring antibiotic therapy.

5. History of or active inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).

6. Had major surgery within 28 days prior to study enrollment. Participants must have fully recovered from the effects of prior surgery in the opinion of the treating Investigator.

7. Inadequate organ function, evidenced by the following laboratory results:

   1. Absolute lymphocyte count < institutional ULN.
   2. Absolute neutrophil count (ANC) < 1,500 cells/mm3.
   3. Platelet count < 100,000 cells/mm3.
   4. Total bilirubin greater than the upper limit of normal (ULN; unless the participant has documented Gilbert's syndrome).
   5. Aspartate aminotransferase (AST [SGOT]) or ALT (SGPT) > 1.5 × ULN.
   6. Alkaline phosphatase (ALP) levels > 2.5 × ULN.
   7. Hemoglobin < 9.0 g/dL.
   8. Serum creatinine > 2.0 mg/dL or 177 μmol/L or creatinine clearance < 40 mL/min (using the Cockcroft-Gault formula below): Female = [(140 - age in years) × weight in kg × 0.85] / [72 × serum creatinine in mg/dL] Male = [(140 - age in years) × weight in kg × 1.00] / [72 × serum creatinine in mg/dL]

8. Have any of following:

   1. Cirrhosis at a level of Child-Pugh B (or worse);
   2. Cirrhosis (any degree) and a history of hepatic encephalopathy; or
   3. Clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis.

9. Participation in an investigational drug study or history of receiving any investigational treatment within 30 days prior to the start of treatment on this study, except for hormone lowering therapy in participants with hormone-sensitive cancer.

10. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol.

11. Pregnant and nursing women.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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40 participants in 6 patient groups

Cohort 1

Other group

Description:

Patients with any of the cancers listed below who have progressed on or after single-agent checkpoint inhibitor therapy after experiencing an initial complete response (CR) or partial response (PR) while taking a checkpoint inhibitor. 1a - Non-small cell lung cancer 1b - Small cell lung cancer 1c - Urothelial carcinoma 1d - Head and neck squamous cell carcinoma 1e - Merkel cell carcinoma 1f - Melanoma 1g - Renal cell carcinoma 1h - Gastric cancer 1i - Cervical cancer 1j - Hepatocellular carcinoma 1k - Microsatellite instability-high or mismatch repair deficient solid tumor cancer or colorectal cancer

Treatment:

Drug: N-803 + Durvalumab

Drug: N-803 + Nivolumab

Drug: N-803 + Avelumab

Drug: N-803 + Atezolizumab

Drug: N-803 + Pembrolizumab

Cohort 2

Other group

Description:

Patients with NSCLC whose tumors have high PD-L1 expression (TPS ≥ 50%) and who relapsed on a PD-1 checkpoint inhibitor after experiencing an initial CR or PR when they received checkpoint inhibitor as a single-agent for first-line treatment.

Treatment:

Drug: N-803 + Nivolumab

Drug: N-803 + Pembrolizumab

Cohort 3

Other group

Description:

Patients with NSCLC who had an initial CR or PR but subsequently relapsed on maintenance PD-1 checkpoint inhibitor therapy when they initially received checkpoint inhibitor therapy in combination with chemotherapy as first-line treatment.

Treatment:

Drug: N-803 + Nivolumab

Drug: N-803 + Pembrolizumab

Cohort 4

Experimental group

Description:

Patients who are currently receiving PD-1/PD-L1 checkpoint inhibitor therapy and have disease progression after experiencing stable disease (SD) for at least 6 months during their previous treatment with PD-1/PD-L1 checkpoint inhibitor therapy.

Treatment:

Drug: N-803 + Durvalumab

Drug: N-803 + Nivolumab

Drug: N-803 + Avelumab

Drug: N-803 + Atezolizumab

Drug: N-803 + Pembrolizumab

Cohort 5

Experimental group

Description:

Patients that have experienced disease progression by Investigator-assessment per irRECIST while receiving treatment in Cohorts 1-4.

Treatment:

Drug: N-803 + Nivolumab + PD-L1 t-haNK

Drug: N-803 + Durvalumab + PD-L1 t-haNK

Drug: N-803 + Avelumab + PD-L1 t-haNK

Drug: N-803 + Pembrolizumab + PD-L1 t-haNK

Drug: N-803 + Atezolizumab + PD-L1 t-haNK

Cohort 6

Experimental group

Description:

Patients who have progressed after an initial response (CR or PR) to a PD-1/PD-L1 checkpoint inhibitor but now exhibit acquired resistance. They have received exactly one line of anti-PD-1 or anti-PD-L1 therapy (either pembrolizumab or nivolumab) for advanced NSCLC (Stage IV or recurrent).

Treatment:

Drug: N-803 + Docetaxel + Pembrolizumab

Drug: N-803 + Docetaxel + Nivolumab