Patient case: 32-year-old female with inflammatory myofibroblastic tumor; genetic feature: RANBP2-ALK fusion

Clinical trial: A Dose Escalation and Cohort Expansion Study of CD122-Biased Cytokine (NKTR-214) in Combination With Anti-PD-1 Antibody (Nivolumab) or in Combination With Nivolumab and Anti-CTLA4 Antibody (Ipilimumab) in Patients With Select Advanced or Metastatic Solid Tumors

Summary: In this four part study, NKTR-214 will be administered in combination with nivolumab in Parts 1 & 2, and with nivolumab and ipilimumab in Parts 3 & 4. In Part 1, the safety, efficacy and recommended Phase 2 dose (RP2D) of NKTR-214 in combination with nivolumab will be determined. In Part 2, the clinical benefit, safety, and tolerability of combining NKTR-214 with nivolumab at the RP2D in select patients with Melanoma, Renal Cell Carcinoma, Non-Small Cell Lung Cancer, Urothelial Carcinoma, or Triple Negative Breast Cancer. In Part 3, the safety, efficacy and RP2D of NKTR-214 in combination with nivolumab and ipilimumab will be determined. In Part 4, the clinical benefit, safety, and tolerability of the triplet combination will be evaluated in select patients with RCC or NSCLC. All three drugs target the immune system and may act synergistically to promote anti-cancer effects.

Detailed description: NKTR-214 is a cytokine (investigational agent) that is designed to target CD122, a protein which is found on certain immune cells (known as CD8+ T Cells and Natural Killer Cells) to expand these cells to promote their anti-tumor effects. Nivolumab is a full human monoclonal antibody that binds to a molecule called PD-1 (programmed cell death protein 1) on immune cells and promotes anti-tumor effects.
  Part 1: Dose escalation of NKTR-214 in combination with nivolumab. A total of 38 eligible patients were enrolled into one of five dose regimens of NKTR-214 in combination with nivolumab (0.006 mg/kg NKTR-214 every 3 weeks (q3w) with 240 mg nivolumab every two weeks (q2w), 0.003 mg/kg NKTR-214 q2w with 240 mg nivolumab q2w, 0.006 mg/kg NKTR-214 q2w with 240 mg nivolumab q2w, 0.006 mg/kg NKTR-214 q3w with 360 mg nivolumab q3w, 0.009 mg/kg NKTR-214 q3w with 360 mg nivolumab q3w). The first part of the study evaluated the safety and efficacy profile of the combination and it was determined that a dose of 0.006 mg/kg NKTR-214 q3w with 360 mg nivolumab q3w, was the Recommended Phase 2 Dose (RP2D), to be studied in Part 2 of the study.
  Part 2: Dose expansion of NKTR-214 in combination with nivolumab. Patients across a total of five specific tumor types (Melanoma, Renal Cell Carcinoma (RCC), Non-Small Cell Lung Cancer (NSCLC), Urothelial Carcinoma, and Triple Negative Breast Cancer (TNBC)) will be enrolled to receive the RP2D of NKTR-214 in combination with nivolumab. Approximately 350 eligible patients who are either Immuno-oncology (I-O) therapy naïve or anti-PD-1 or anti-PD-L1 relapsed/refractory will be enrolled in the Dose Expansion (Part 2) into one of thirteen cohorts as follows:
  -  Melanoma:1st-line
  -  Melanoma: 2nd- and 3rd-line anti-PD-1 or anti-PD-L1 relapsed/refractory
  -  RCC: 1st-line I-O therapy naïve
  -  RCC: 2nd- and 3rd-line anti-PD-1 or anti-PD-L1 relapsed/refractory
  -  NSCLC 1st-line (PD-L1 ≥ 50%)
  -  NSCLC 1st-line (PD-L1< 1%)
  -  NSCLC 1st-line (PD-L1 ≥ 1% - < 50%)
  -  NSCLC: 2nd-line I-O therapy naïve
  -  NSCLC: 2nd- and 3rd-line anti-PD-1 or anti-PD-L1 relapsed/refractory
  -  Urothelial Carcinoma (Bladder): 1st-line I-O therapy naïve
  -  Urothelial Carcinoma (Bladder): 1st-line cisplatin-ineligible I-O therapy naïve
  -  Urothelial Carcinoma (Bladder): 3rd-Line anti-PD-1 or anti-PD-L1 relapsed/refractory
  -  TNBC: 1st- and 2nd-line I-O therapy naïve
  Part 3: Schedule finding of NKTR-214 in combination with nivolumab and ipilimumab. During this part of the study, the safety and tolerability, and efficacy of the triplet combination will be evaluated in approximately 30 treatment naïve patients with metastatic RCC or NSCLC to determine a RP2D and administration schedule. The first schedule to be evaluated Cohort A, is NKTR-214 0.006 mg/kg and nivolumab 360 mg q3w with the addition of ipilimumab 1 mg/kg q6w.
  Part 4: Dose expansion of NKTR-214 in combination with nivolumab and ipilimumab. Approximately 60 first line RCC or NSCLC patients (26-38 patients per indication) will be enrolled at the RP2D determined in Part 3 to further evaluate the safety, tolerability and efficacy of the triple combination.
  All patients enrolled in the study will be closely monitored to determine if there is response to the treatment as well as for any side effects that may occur. The efficacy of the combination will be assessed using objective response rate (ORR). Exploratory immunological biomarkers in plasma and tumor samples will evaluate immune activation.

Eligibility: INCLUSION CRITERIA - For Parts 1-4:
  -  Willing and able to provide written informed consent
  -  Histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy such as surgical resection) or metastatic melanoma, RCC, NSCLC, urothelial carcinoma, or TNBC
  -  Male or female patients, age 18 years or older at the time of signing the informed consent form (ICF)
  -  Life expectancy > 12 weeks
  -  Patients must not have received prior interleukin-2 (IL-2) therapy
  -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  -  Measurable disease per RECIST 1.1
  -  Demonstrated adequate organ function within 28 days of treatment initiation
  -  Oxygen saturation ≥ 92% on room air.
  -  Subjects must be recovered from the effects of any prior chemotherapy, immunotherapy, other prior system anticancer therapy, radiotherapy, or surgery. Clinically significant toxic effect(s) of the most recent prior chemotherapy must be resolved to Grade 1 or less (except alopecia and sensory neuropathy).
  -  Women of childbearing potential must agree to use highly effective methods of birth control. All participants must agree to use double barrier contraception during study participation for at least 6 months after the last dose of study drugs.
  -  Patients with stable brain metastases may be enrolled if certain criteria are met.
  -  Fresh and archival tumor tissue available
  -  Additional criteria may apply.
  INCLUSION CRITERIA - For Part 2:
  -  MELANOMA:
  -  Histologically confirmed stage III (unresectable) or stage IV melanoma, as per American Joint Committee on Cancer (AJCC) staging system
  -  Ocular melanoma will be excluded
  -  Melanoma Subpopulation A 1st-line (1L):
  -  Have not received prior anti-cancer therapy for advanced or metastatic melanoma
  -  Known BRAF status, or consent to testing, as per regionally acceptable V600 mutational status testing
  -  Melanoma Subpopulation B (2nd- and 3rd-line (2-3L), anti-PD-1 or anti-PD-L1 therapy relapsed/refractory):
  -  Patients must have received only 1 prior line of therapy with an anti-PD-1 or anti-PD-L1 containing regimen, which must be their most recent anti-cancer treatment.
  -  Patients must have confirmed radiographic disease progression no earlier than 4 weeks after initial disease progression but within 3 months from last dose of anti-PD-1 or anti PD-L1 containing regimen. Patients must consent to providing pre-study scans (if available) to confirm radiographic progression.
  -  Patients may have received no more than 1 prior anti-angiogenic therapy or cytotoxic chemotherapy regimen.
  -  RENAL CELL CARCINOMA (RCC):
  -  Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC stage IV) RCC
  -  Histologically confirmed RCC with a clear-cell component.
  -  RCC Subpopulation A (1L):
  -  1L, patients may have not received prior anti-cancer therapy for advanced or metastatic RCC.
  -  RCC Subpopulation B (2-3L, anti-PD-1 or anti-PD-L1 relapsed/refractory):
  -  Patients must have confirmed radiographic disease progression no earlier than 4 weeks after initial disease progression but within 3 months from last dose of anti-PD-1 or anti-PD-L1 containing regimen. Patients must consent to providing pre-study scans (if available) to confirm radiographic progression.
  -  Patients may have received no more than 1 prior anti-angiogenic therapy or cytotoxic chemotherapy regimen.
  -  NON-SMALL CELL LUNG CANCER (NSCLC):
  -  Histologically confirmed or cytologically confirmed diagnosis of stage IV NSCLC
  -  Patients with nonsquamous NSCLC must lack epidermal growth factor receptor (EGFR)-sensitizing mutation and/or anaplastic lymphoma kinase (ALK) translocation
  -  NSCLC Subpopulation A (1L):
  -  1L, patients must not have received prior anti-cancer therapy for advanced or metastatic NSCLC. Patients must have known PD-L1 status as per validated immunohistochemistry testing. Up to 20 patients will be enrolled in each subgroup:
  -  PD-L1 negative (PD-L1 < 1%),
  -  PD-L1 positive (PD-L1 ≥ 50%),
  -  PD-L1 low/intermediate (PD-L1 ≥ 1% - < 50%).
  -  For patients who do not have known PD-L1 status, testing must be done using an FDA-approved PD-L1 test.
  -  NSCLC Subpopulation B (2L, I-O therapy naïve):
  -  2L, patients must have experienced disease recurrence or progression during or after one prior platinum doublet-based chemotherapy regimen for advanced or metastatic disease. Patients who received platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation therapy given for locally advanced disease and developed recurrent (local or metastatic) disease within 6 months of completing therapy are eligible. Patients must not have received any prior immune-oncology regimens, including but not limited to checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways, indoleamine 2,3 dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or other cytokine therapies.
  -  NSCLC Subpopulation C (2-3L, anti-PD-1 or anti-PD-L1 relapsed/refactory):
  -  Patients must have received only 1 prior line of therapy with an anti-PD-1 or anti-PD L1 containing regimen, which must be their most recent anti-cancer treatment.
  -  Patients may have progressed on at least one line of therapy that contains platinum-based chemotherapy in the metastatic setting or post platinum-based chemotherapy in an adjuvant setting with progression < 6 months
  -  Patients must have confirmed radiographic disease progression no earlier than 4 weeks after initial disease progression but within 3 months from last dose of anti-PD-1 or anti-PD-L1 containing regimen. Patients must consent to providing pre-study scans (if available) to confirm radiographic progression.
  -  UROTHELIAL CARCINOMA (UC)
  -  Histologically or cytologically documented locally advanced or transitional cell carcinoma of the urothelium including renal pelvis, ureters, urinary bladder, or urethra. Patients with mixed histologies are required to have a dominant transitional cell pattern.
  -  For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval of more than 12 months between the last treatment administration and the date of recurrence is required to be considered treatment naive in the metastatic setting.
  -  UC Subpopulation A (1L)
  -  Enrollment of urothelial carcinoma 1L patients will target accrual of up to 20 patients who are cis-ineligible and up to 20 patients, who after consultation with the Investigator, choose to forego front-line chemotherapy
  -  Treatment naive and cisplatin-eligible patients who refuse chemotherapy standard of care.
  -  UC Subpopulation B (1L) cisplatin-ineligible
  -  Treatment naive and cisplatin-ineligible patients who meet at least one of the following criteria:
  -  Creatinine clearance (calculated or measured) < 60 mL/min Cisplatin-ineligible patients must have a creatine clearance <60 mL/min and GFR ≥ 15 mL/min
  -  Common Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade ≥ 2 audiometric hearing loss
  -  CTCAE v4.03 Grade ≥ 2 peripheral neuropathy
  -  New York Heart Association (NYHA) Class III heart failure
  -  No prior chemotherapy for inoperable locally advanced or metastatic urothelial carcinoma. Prior local intravesical chemotherapy is allowed if completed at least 4 weeks prior to the initiation of study treatment.
  -  Patients must not have received any prior immune-oncology regimens, including but not limited to checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways, indoleamine 2,3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or other cytokine therapies.
  -  UC Subpopulation C (3L, anti-PD-1 or anti-PD-L1 relapse/refractory)
  -  Patients must have progressed on only one prior line of therapy that contains platinum-based chemotherapy in the metastatic setting or post platinum-based chemotherapy in an adjuvant setting with progression < 6 months.
  -  Patients must have received only one prior line of therapy with an anti-PD-1 or anti-PD-L1 containing regimen, which must be their most recent anti-cancer treatment.
  -  Patients must have confirmed radiographic disease progression no earlier than 4 weeks after initial disease progression but within 3 months from last dose of anti-PD-1 or anti-PD-L1 containing regimen. Patients must consent to providing pre-study scans (if available) to confirm radiographic progression.
  -  TRIPLE-NEGATIVE BREAST CANCER (1-2L, I-O therapy naïve)
  -  Less than 1% of tumor cell nuclei test positive for estrogen and progesterone receptors determined by using standard immunohistochemistry (IHC)
  -  Human epidermal growth factor 2 (HER2) negative as determined by local pathologist, using IHC or in situ hybridization
  -  Patients may have received only 1 prior line of therapy with chemotherapy, adjuvant setting excluded, or patient refuses standard of care.
  -  Must not have received any prior immune-oncology regimens, including but not limited to checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways, indoleamine 2, 3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or other cytokine therapies.
  INCLUSION CRITERIA - For Parts 3 and 4:
  -  RENAL CELL CARCINOMA (1L):
  -  Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC stage IV) RCC.
  -  Histologically confirmed RCC with a clear-cell component.
  -  Patients must not have received prior anti-cancer therapy for advanced or metastatic RCC
  -  NON-SMALL CELL LUNG CANCER (1L):
  -  Histologically confirmed or cytologically confirmed diagnosis of stage IV NSCLC
  -  Patients with nonsquamous NSCLC must lack epidermal growth factor receptor (EGFR)-sensitizing mutation and/or anaplastic lymphoma kinase (ALK) translocation.
  -  Patients must not have received prior anti-cancer therapy for advanced or metastatic NSCLC.
  EXCLUSION CRITERIA - For Parts 1-4:
  -  Use of an investigational agent or an investigational device within 28 days before administration of first dose of NKTR--214
  -  Females who are pregnant or breastfeeding
  -  Participants who have an active autoimmune disease requiring systemic treatment within the past 3 months or have a documented history of clinically severe autoimmune disease that requires systemic steroids or immunosuppressive agents
  -  History of organ transplant that requires use of immune suppressive agents
  -  History of allergy or hypersensitivity to study drug components
  -  Active malignancy not related to the current diagnosed malignancy
  -  Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis
  -  Prior surgery or radiotherapy within 14 days of therapy
  -  Participants who have had < 28 days since the last chemotherapy, biological therapy, or < 14 days from approved tyrosine kinase inhibitor (TKI) therapy (sunitinib, sorafenib, vemurafenib, dabrafenib, cobimetinib, erlotinib, gefitinib, afatinib, osimertinib), or systemic or inhaled steroid therapy at doses greater than 10mg of prednisone or equivalent before administration of the first dose of study medication
  -  Participant's inability to adhere to or tolerate protocol or study procedures
  -  Additional criteria may apply.

Relevance to patient case: not relevant