Phase 1B Trial of Intratumoral Cisplatin for Stage IV Lung Cancer

Rationale:

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States. The mainstay of therapy for lung cancer remains platinum-based chemotherapy. One of the most commonly used agents is cisplatin, due to the fact that it is highly toxic to cancer cells. Cisplatin binds with DNA, cross-linking strands and thereby inhibiting mitosis, which in turn leads to apoptosis and death of the cell. However, it has more recently been recognized that cisplatin has immunomodulatory effects that extend beyond those related merely to cell death. Cisplatin has been shown to upregulate major histocompatibility complex (MHC class 1), promote the recruitment and proliferation of effector cells, upregulate the activity of cytotoxic effector cells, and downregulate the immunosuppressive environment. Importantly, mechanisms by which cisplatin modulates the immune system may be present even at sublethal doses. In fact, the addition of an intravenous (i.v.) platinum agent to pembrolizumab increases the efficacy of immune checkpoint blockade in Stage IV NSCLC.

Although many standard regimens for the treatment of NSCLC include a platinum agent, this approach is associated with significant toxicity. Systemic i.v. cisplatin is associated with greater than 40 untoward effects; the most common is nephrotoxicity, but may commonly include gastrointestinal, hematologic, cardiac, and hepatic events. These off-target effects greatly impair patient quality of life and tolerance of the drug, which in turn limits the dose and frequency at which the medication can be given. In Stage IV NSCLC there is evidence that platinum-based chemotherapy may hasten death compared to palliative care. Adding i.v. chemotherapy to immunotherapy results in a dramatic and synergistic increase in adverse events. In fact, the FDA guidance document for cisplatin highlights a feature of this drug that is atypical for chemotherapeutics, namely that it is more highly absorbed in normal tissues than in tumor tissue.

Direct intratumoral delivery of cisplatin thus has the potential to dramatically reduce adverse systemic effects while providing an immunoadjuvant effect to optimize the efficacy of subsequent immunotherapy for Stage IV NSCLC.

One approach for direct intratumoral delivery is endobronchial ultrasound-guided transbronchial needle injection of cisplatin (EBUS-TBNI cisplatin). A bronchoscope with an integrated ultrasound is used to deliver cisplatin, through a needle, directly into tumors that lie next to the airway. This therapy has been evaluated as treatment for recurrent lung cancer in a previously radiated field. Patients undergo one bronchoscopic procedure per week (one cycle) for 3 weeks. Our prior multicenter study of EBUS-TBNI cisplatin demonstrated a 71% complete or partial response of the treated tumor. Given the demonstrated tumor cytotoxicity of EBUS-TBNI cisplatin for recurrent cancer, the potential ability of cisplatin to augment the immune response, and the systemic toxicity associated with IV delivery, it is critical to evaluate EBUS-TBNI cisplatin as neoadjuvant therapy in the first-line setting. Importantly, this approach is additive to standard of care, does not replace any current therapeutic approach, and has the potential to dramatically reduce time-to-treatment and improve immunotherapy efficacy.

In Phase 1B we will test dosing based on tumor volume and morphology over the course of 3 procedures, 1 week apart, prior to the initiation of systemic therapy. Three intratumoral cisplatin deliveries, with the first typically given in the same procedural instance as diagnosis, was chosen as the treatment course since it would not delay standard of care therapy. During each of the procedures either a low or high microvascular region will be targeted for delivery.

HYPOTHESIS:

Delivery of an image-enabled, computationally selected, dose of intratumoral cisplatin into regions of low microvascular density within a lung tumor, will be safe and result in improved drug retention

STUDY POPULATION:

Patients eligible for consent will be age 18 or older Eastern Cooperative Oncology Group (ECOG) performance score 0-2 Patients will have known or suspected Stage IV, metastatic, non-small cell lung cancer (NSCLC) after multidisciplinary review

STUDY DESIGN:

This a randomized, single blind, 3+3, Phase 1 study of Intratumoral Neoadjuvant Cisplatin for Stage IV Lung Cancer delivered via EBUS-TBNI. The primary endpoint is safety. This study utilizes a within-patient approach with all patients undergoing three EBUS-TBNI procedures, 1 week apart, where the dose will be delivered into either a low or high microvascular region (randomized).

The initial dose level will be 95% tumor coverage. Tumor morphology and volume will be obtained from each participant's preoperative CT scan. The dose to be delivered will be calculated using the validated computational model based on the goal % tumor coverage (e.g. dose needed to cover 95% of the tumor).

The dose escalation cohort is 98%. The dose de-escalation cohort is 90% coverage). Escalation/de-escalation will occur in standard 3+3 design.

ENDPOINT EVALUATION:

Primary Endpoint:

Safety (dose limiting toxicity, DLT), as defined by CTCAE (Common Terminology Criteria for Adverse Events) v 6.0. CTCAE grade 3 or above will be considered a DLT. There will be no dose escalation but standard 3+3 dose reduction will be performed as described in the statistical section. Briefly, any CTCAE grade 3 event within a patient's treatment regimen will result in discontinuation from the study and no further procedures (if the participant has not completed the treatment regimen).

Secondary Endpoints:

• Retained cisplatin mass by low versus high microvascular regions.

2.5.1 Inclusion criteria

• Age 18 years or above
• Eastern Cooperative Oncology Group (ECOG) performance score 0-2
• Have known or suspected metastatic NSCLC at time of enrollment (including patients who progress on initial therapy or are found to have metastatic disease during therapy and are not excluded
• Patient is able and willing to provide informed consent.
• Rapid on-site cytopathologic examination (ROSE) performed during the procedure (if not previously diagnosed) and returns likely NSCLC. No injection will be performed if ROSE is non-diagnostic.
• A CT scan of the chest (with or without contrast) within the prior 3 months.
• The presence of an EBUS accessible target site determined by a treating investigator. These may be primary lung cancers or metastatic sites (including when a lymph node station has been replaced by metastatic tumor), that are accessible by EBUS.
• MDC agreement of likely Stage IV NSCLC (confirmation from at minimum a Medical Oncologist and Radiation Oncologist on clinical stage).
• Patients must have adequate organ and marrow function as defined below:

• Leukocytes ≥3,000/mcL
• Platelets ≥100,000/mcL
• Total bilirubin ≤ institutional upper limit of normal (ULN)
• AST(SGOT)/ALT(SGPT) ≤ institutional ULN
• Creatinine ≤ institutional ULN

2.5.2 Exclusion criteria

• Use of an investigational agent in prior 30 days
• Pregnancy/lactation (pregnancy test to be performed by pre-op as part of standard of care for women of child-bearing age as defined by UVMMC Policy NPREP16)
• Treatment with intravenous cytotoxic chemotherapy within the past 14 days
• Allergy to cisplatin or its derivatives
• Allergy to iodinated contrast
• Patient not appropriate for the research study based on physician discretion