This is a Phase IIb, multicohort, open-label multicenter study of combination immunotherapies
in patients who have previously received treatment with PD-1/PD-L1 immune checkpoint
inhibitors. All patients in Cohorts 1-4 will receive the combination treatment of PD-1/PD-L1
checkpoint inhibitor plus N-803 for up to 17 cycles. Each cycle is six weeks in duration.
Some patients who experience disease progression while on study in Cohorts 1-4 may roll over
into Cohort 5 and receive combination therapy with a PD-1/PD-L1 checkpoint inhibitor, N-803,
and PD-L1 t-haNK cellular therapy for up to an additional 17 cycles. Each cycle is six weeks
in duration. All patients will receive N-803 once every 3 weeks. Patients will also receive
the same checkpoint inhibitor that they received during their previous therapy. Radiologic
evaluation will occur at the end of each treatment cycle. Treatment will continue for up to 2
years, or until the patient experiences confirmed progressive disease or unacceptable
toxicity, withdraws consent, or if the Investigator feels it is no longer in the patient's
best interest to continue treatment. Patients will be followed for disease progression,
post-therapies, and survival through 24 months past administration of the first dose of study
drug.
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
