Brief Title: QUILT-3.055: A Study of ALT-803 in Combination With PD-1/PD-L1 Checkpoint Inhibitor in Patients With Advanced Cancer

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Objective Response Rate

Primary Outcome 1 - Timeframe: 24 months

CONDITION

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ELIGIBILITY

Inclusion Criteria:
1. Signed Written Informed Consent
• Voluntary written informed consent and HIPAA authorization and agree to comply with all protocol-specified procedures and follow-up evaluations

- 2. Target Population
1. Cohort 1 will enroll patients who have Investigator-assessed disease progression on or after single-agent checkpoint inhibitor therapy after experiencing an initial response (ie, Investigator-assessed CR or PR) while taking checkpoint inhibitor therapy. Patients will be enrolled into distinct cohorts (1a-1k) based on cancer type.
Patients must have been treated with checkpoint inhibitor therapy after progressing on SoC therapy for their disease, as per FDA indication detailed below:

- * 1a - For metastatic squamous or nonsquamous NSCLC with progression on or after nivolumab, pembrolizumab, or atezolizumab, initial SoC therapy must have been for disease with progression on or after one prior platinum doublet-based chemotherapy regimen. Patients with EGFR or ALK genomic tumor aberrations should have had disease progression on FDA-approved targeted therapy for these aberrations prior to receiving checkpoint inhibitor.

- * 1b - For metastatic SCLC with disease progression on or after nivolumab or pembrolizumab monotherapy, initial SoC treatment must have been for disease with progression after platinum-based chemotherapy and at least one other line of therapy prior to receiving checkpoint.

- * 1c - Locally advanced or metastatic urothelial carcinoma as follows:

- * For patients with progression on or after nivolumab monotherapy, initial SoC must have been for disease with progression on or after platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-based chemotherapy.

- * For patients with disease progression on or after pembrolizumab, initial SoC therapy may have been for locally advanced or metastatic urothelial carcinoma ineligible for cisplatin-containing chemotherapy with PD-L1 tumor expression of CPS ≥ 10 (as determined by FDA-approved test), OR metastatic urothelial carcinoma not eligible for any platinum-containing chemotherapy regardless of PD-L1 status, OR locally advanced or metastatic urothelial carcinoma with progression on or after platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-based chemotherapy.

- * For patients with disease progression on or after atezolizumab, initial SoC therapy may have been for locally advanced or metastatic urothelial carcinoma not eligible for cisplatin-based chemotherapy that expresses PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 5% of the tumor area, as determined by an FDA-approved test), OR not eligible for cisplatin-based chemotherapy regardless of PD-L1 status, OR with progression on or after platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-based chemotherapy.

- * For patients with disease progression on or after avelumab, initial SoC therapy may have been for locally advanced or metastatic urothelial carcinoma with progression on or after platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-based chemotherapy.

- * For patients with disease progression on or after durvalumab, initial SoC therapy may have been for disease with progression on or after platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-based chemotherapy.

- * 1d - Recurrent or metastatic HNSCC as follows:

- * For patients with disease progression on or after nivolumab monotherapy, initial SoC treatment must have been for disease with progression on or within 6 months of a platinum-based therapy administered in the adjuvant, neoadjuvant, primary (unresectable locally advanced), or metastatic setting.

- * For patients with disease progression on or after pembrolizumab monotherapy, initial SoC treatment must have been for disease with progression on or after platinum-based chemotherapy, or after platinum-based chemotherapy administered as part of induction, concurrent, or adjuvant therapy.

- * 1e - For histologically confirmed metastatic MCC with progression on or after avelumab or pembrolizumab, initial SoC therapy must have been for disease with progression on or after chemotherapy administered for distant metastatic disease; OR recurrent locally advanced or metastatic MCC not treated with prior systemic therapy for advanced disease.

- * 1f - Metastatic melanoma as follows:

- * For patients with disease progression on or after nivolumab administered as a single agent, in combination with ipilimumab, or in the adjuvant setting, initial SoC treatment must have been for unresectable or metastatic melanoma with progression on or after ipilimumab treatment, and if BRAF V600 mutation positive, a BRAF inhibitor; OR BRAF V600 wild-type unresectable or metastatic melanoma previously untreated in the metastatic setting; OR previously untreated, unresectable, or metastatic melanoma not previously treated with anti-CTLA4 antibody; OR completely resected melanoma with lymph node involvement, or stage IIIB/C or stage IV metastatic disease.

- * For patients with disease progression on or after pembrolizumab therapy, initial SoC treatment must have been for unresectable or metastatic melanoma with no prior ipilimumab, and no more than 1 prior systemic treatment for metastatic disease. Patients with BRAF V600E mutation-positive melanoma were not required to have received prior BRAF inhibitor therapy; OR unresectable or metastatic melanoma with progression, refractory to ≥ 2 doses of ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor, and disease progression within 24 weeks following the last dose of ipilimumab.

- * 1g - For advanced RCC with progression on or after nivolumab monotherapy, initial SoC therapy must have been for disease that progressed after 1 or 2 prior anti-angiogenic therapy regimens. For intermediate or poor risk previously untreated advanced RCC, patients must have progressed on or after nivolumab + ipilimumab.

- * 1h - For recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with progression on or after pembrolizumab, initial SoC therapy must have been for disease that progressed on or after ≥ 2 prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy. Tumors must express PD-L1 (combined positive score [CPS] ≥ 1), as determined by an FDA-approved test.

- * 1i - For recurrent or metastatic cervical cancer with progression on or after pembrolizumab, initial SoC therapy must have been for disease that progressed on or after chemotherapy. Tumors must express PD-L1 (CPS ≥ 1), as determined by an FDA-approved test.

- * 1j - For HCC with progression on or after pembrolizumab, initial SoC treatment must have been for disease that progressed on or after sorafenib or intolerant to sorafenib. Patients must have had measureable disease and Child-Pugh class A liver impairment. For HCC with progression on or after nivolumab administered as a single agent or in combination with ipilimumab, initial SoC treatment must have been for histologically confirmed HCC with progression on sorafenib or intolerant to sorafenib, and Child-Pugh class A.

- * 1k -Unresectable or metastatic MSI-H or dMMR solid tumors as follows:

- * For patients with progression on or after nivolumab administered as a single agent or in combination with ipilimumab, initial SoC therapy must have been for MSI-H or dMMR metastatic CRC with progression on or after treatment with a fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

- * For patients with progression on or after pembrolizumab, initial SoC therapy must have been for unresectable or metastatic MSI-H or dMMR solid tumors with progression after prior treatment and no satisfactory alternative treatment options; OR unresectable or metastatic MSI-H or dMMR CRC with progression after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

- 2. For cohort 2, patients with NSCLC whose tumors have high PD-L1 expression (TPS ≥ 50%) and who have Investigator-assessed disease progression on a PD-1/PD-L1 checkpoint inhibitor after experiencing an initial Investigator-assessed CR or PR when they received checkpoint inhibitor as a single-agent for first-line treatment.

- 3. For cohort 3, patients with NSCLC who had an initial Investigator-assessed CR or PR but subsequently relapsed (ie, Investigator-assessed disease progression) on maintenance PD-1/PD-L1 checkpoint inhibitor therapy when they initially received checkpoint inhibitor therapy in combination with chemotherapy as first-line treatment.

- 4. For cohort 4, patients with NSCLC, HNSCC, RCC, or urothelial carcinoma who are currently receiving PD-1/PD-L1 checkpoint inhibitor therapy and have Investigator-assessed disease progression after experiencing SD for at least 6 months during their previous treatment with PD-1/PD-L1 checkpoint inhibitor therapy.

- 5. For cohort 5, patients that have experienced disease progression by Investigator assessment per irRECIST while receiving treatment in cohorts 1-4.

- 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- 7. Measurable disease by CT or MRI, as defined by RECIST 1.1, except Cohort 5, where non-measurable disease is also allowed

- 8. Treatment of at least 3 months (cohort 1-3) or at least 6 months (cohort 4) with checkpoint inhibitor and Investigator-assessed CR or PR (for cohorts 1-3 only) or SD (for cohort 4 only) and ≤ 6 weeks of treatment interruption (cohorts 1-4) immediately prior to study enrollment; treatment in cohort 5 must occur within 1 year of discontinuation from cohorts 1-4.

- 9. Patients with genomic tumor aberrations should have received prior treatment with an FDA-approved targeted therapy (if available)

- 10. Adequate organ system function within 14 days of baseline:
* ANC ≥ 1500 cells/µL (≥1.5 x 10^9 cells/L)

- * Platelets ≥ 100,000 cells/µL (≥100 x 10^9 cells/L)

- * Hemoglobin > 8 g/dL

- * Total bilirubin < 1.0 x ULN - * AST < 1.5 x ULN - * ALT < 1.5 x ULN - * eGFR > 45 mL/min

- 3. Age and Reproductive Status
1. Men and women, ≥ 18 years of age

- 2. Women of childbearing potential (WOCBP) must adhere to using a medically accepted method of birth control up to 28 days prior to screening and agree to continue its use during the study or be surgically sterilized (e.g., hysterectomy or tubal ligation) and males must agree to use barrier methods of birth control while on study. WOCBP must agree to use effective contraception during treatment and for at least 5 months following the last dose of study treatment.

- 3. Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test during Screening and a negative urine pregnancy test within 24 hours prior to first dose of study treatment (cohorts 1-4); subjects in cohort 5 must have a negative urine pregnancy test at screening and baseline. Non-childbearing is defined as greater than one year postmenopausal or surgically sterilized.
Exclusion Criteria:
1. Target Disease Exceptions
a. Patients with CNS metastases with the following exceptions:

- * Patient untreated CNS metastases with 4 or fewer sites of disease, with no single site larger than 20mm, are eligible if they are asymptomatic and not requiring steroids at any dose. Patients with asymptomatic CNS metastases may be treated with radiosurgery before or during therapy on trial without treatment delays.

- * Patients with treated, symptomatic CNS metastases are eligible if they are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to registration AND either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent).

- * Patients enrolling in cohort 5

- 2. Medical History and Concurrent Diseases
1. New York Heart Association (NYHA) Class III or IV heart failure, uncontrollable supraventricular arrhythmias, any history of a ventricular arrhythmia, or other clinical signs of severe cardiac dysfunction

- 2. Symptomatic congestive heart failure, unstable angina pectoris, or myocardial infarction within 6 months of enrollment

- 3. Known autoimmune disease requiring active treatment. Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses < 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease - 4. History of interstitial lung disease and/or immune mediated pneumonitis. - 5. Known HIV-positive - 6. Active systemic infection requiring parenteral antibiotic therapy - 7. Positive hepatitis C serology or active hepatitis B infection - 8. Any ongoing toxicity from prior anti-cancer treatment that, in the judgement of the investigator, may interfere with study treatment. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must resolve to grade 1 (NCI CTCAE version 4) or baseline prior to enrollment. Eligible patients must not require more than 10 mg/day prednisone (or equivalent dose). - 9. Previous malignancies (except non-melanoma skin cancers, in situ bladder cancer, in situ gastric or in situ colon cancers, in situ cervical cancers/dysplasia or breast carcinoma in situ) unless a complete remission was achieved at least 1 year prior to study entry and no additional therapy is required or anticipated to be required during the study period. This exclusion does not apply to patients enrolling in cohort 5. - 10. No other illness that in the opinion of the investigator would exclude the subject from participating in the study - 3. Prohibited Treatments and/or Restricted Therapies
1. Patients in which treatment with PD-1/PD-L1 checkpoint inhibitor is contraindicated

- 2. Patients who have received another investigational agent within the previous 3 months. This exclusion criteria does not apply to patients enrolling in cohort 5.

- 4. Sex and Reproductive Status a. Women who are pregnant or nursing

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

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