Patient case: 45-year-old female with colon cancer; genetic feature: ERBB2 amplification

Clinical trial: A Phase 2 Study of NIR178 in Combination With PDR001 in Patients With Solid Tumors and Non-Hodgkin Lymphoma

Summary: The purpose of this phase 2 study is to evaluate the efficacy and safety of NIR178 in combination with PDR001 in multiple solid tumors and diffuse large B-cell lymphoma (DLBCL) and further explore schedule variations of NIR178 to optimize immune activation through inhibition of A2aR.

Detailed description: The study has four parts: part 1: Multi-arm Bayesian adaptive signal finding design in solid tumors and diffuse large B cell lymphoma (DLBCL); part 2: NIR178 schedule exploration in NSCLC; part 3: Further evaluation of intermittent dosing schedules of NIR178 in combination with PDR001 in additional tumor types, if part 2 identifies an intermittent dosing schedule of NIR178 as warranting further exploration; part 4: A separate safety run-in part will be conducted in Japan in order to adequately characterize the safety and pharmacokinetic profiles of NIR178 as a single-agent.
  Parts 1, 2 and 4 will enroll in parallel. Part 3 will be opened based on the results from part 2.
  Patients enrolled in this study will receive NIR178 either BID continuously or based on the assigned intermittent schedule within 60 minutes prior to PDR001 infusion. PDR001 will be administered via IV infusion over 30 minutes once every 4 weeks. Each treatment cycle is 28 days. Patients enrolled in the Japanese safety run-in part will receive NIR178 as single agent for the first cycle (28 days). If the patients complete cycle 1 without experiencing DLTs, they will initiate combination therapy with PDR001 starting cycle 2 onwards, and continue at the same dose of NIR178.
  Patients will receive treatment with the combination until disease progression (assessed by investigator per immune-related response criteria (irRC) or Cheson 2014, unacceptable toxicity, death or discontinuation from study treatment for any other reason (e.g., withdrawal of consent, start of a new anti-neoplastic therapy or at the discretion of the investigator), otherwise known as End of Treatment.

Eligibility: Inclusion Criteria:
  Male or female patients ≥18 years of age. For Japan only: written consent is necessary both from the patient and his/her legal representative if he/she is under the age of 20 years.
  Histologically documented advanced or metastatic solid tumors or lymphomas
  -  Part 1: histologically confirmed renal cell carcinoma (RCC), pancreatic cancer, urothelial cancer, head and neck cancer, diffuse large B-cell lymphoma (DLBCL), microsatellite stable (MSS) colon cancer, triple negative breast cancer (TNBC) or melanoma
  -  Part 2: histologically confirmed diagnosis of advanced/metastatic NSCLC. For those with mixed histology, there must be a predominant histology
  -  Part 3: histologically confirmed diagnosis of advanced/metastatic NSCLC and one additional tumor type based on emerging data from part 1 of the study.
  Patient (except for those participating in Japanese safety run-in) must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening, and again during therapy on this study.
  o Part 4: Safety run-in part in Japanese patients can enroll any tumor type included in part 1 and 2.
  The collection of recent sample is permitted under the following conditions (both must be met):
  -  Biopsy was collected ≤ 3 months before 1st dose of study treatment and available at the site.
  -  No immunotherapy was given to the patient since collection of biopsy.
  Part 1 - 3 only: Patients (other than those with DLBCL) must previously have received at least 1 and no more than 3 prior lines of therapy for their disease, specifically including the following, unless considered inappropriate for the patient (e.g. safety concern, label contraindication):
  -  Patients with NSCLC must have received a prior platinum-based combination.
  -  Patients with EGFR positive NSCLC with a T790M mutation must have progressed on osimertinib or discontinued due to toxicity.
  -  Patients with head and neck cancer must have received a prior platinum-containing regimen.
  -  Patients with bladder cancer must have received a prior platinum-containing regimen or be ineligible for cisplatin.
  -  Patients with renal cell carcinoma must have received a prior VEGF tyrosine kinase inhibitor (TKI).
  -  Patients with MSS colorectal cancer must have received (or be intolerant to) prior therapy with fluoropyrimidine-oxaliplatin- and irinotecan- based regimens.
  -  Patients with triple negative breast cancer must have received a prior taxane-containing regimen.
  Patients with DLBCL should be limited to those with no available therapies of proven clinical benefit
  o Patients should have had prior autologous hematopoietic stem cell transplantation (auto-HSCT) or determined to be ineligible for auto-HSCT.
  Patients must not have received prior immunotherapy (previous immune checkpoint inhibitors; single agent and/or combination therapy with anti-CTLA-4, anti-PD-1, anti-PD-L1), except for NSCLC patients enrolled in part 3 and Japanese safety run-in part.
  Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral computer tomography (CT) scan, Magnetic Resonance Imaging (MRI), or calipers by clinical exam.
  Other protocol-defined inclusion criteria may apply.
  Exclusion Criteria:
  Ongoing or prior treatment with A2aR inhibitors. Patients previously treated with A2aR inhibitors for non-oncologic indications (e.g. Parkinson's disease) may be considered for enrollment on a case by case basis.
  Current or prior use of immunosuppressive medication within 28 days before the first dose of PDR001, with the exception of intranasal/inhaled corticosteroids or systemic corticosteroids at physiological doses (not exceeding equivalent of 10 mg/day of prednisone) History of another primary malignancy except for:
  -  Malignancy treated with curative intent and with no known active disease ≥2 years before the first dose of study drug and of low potential risk for recurrence
  -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  -  Adequately treated carcinoma in situ without evidence of disease Active or prior documented autoimmune disease within the past 2 years. Patients with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
  More than 3 prior lines of therapy except for Japanese safety run-in part. History of interstitial lung disease or non-infectious pneumonitis Participation in another clinical study with an investigational product during the last 21 days prior to starting on treatment.
  Other protocol-defined exclusion criteria may apply.

Relevance to patient case: not relevant