The Role of Targeted Agents and Their Effects on Lymphocytes and Patient Outcomes

Lead Investigator: Elad Sharon, National Cancer Institute
Title of Proposal Research: The Role of Targeted Agents and Their Effects on Lymphocytes and Patient Outcomes
Vivli Data Request: 5988
Funding Source: None
Potential Conflicts of Interest: None

Summary of the Proposed Research:

The relationship between the immune system and cancer has been of interest to the scientific community for decades. In 1909, Erlich suggested that the immune system plays a critical role in suppressing tumor cell development, termed immunosurveillance. The lymphocyte serves an important role in this process by recognizing non-self cells and mediating cell killing through complex mechanisms. Lymphocytes that infiltrate tumors are known as tumor infiltrating lymphocytes (or TILs) and have also been linked to a more favorable predictor of survival for many tumor types including colorectal cancer, breast cancer, esophageal cancer, ovarian cancer, cervical cancer, and oral squamous cancers. On the other hand, cancer cells have developed an innate ability to escape the immune system targeting foreign cells for destruction by down regulating key players including lymphocytes. Naturally, impairment of host immunity is associated with worse outcomes.

Prior studies have shown that a low lymphocyte count at diagnosis or prior to treatment is linked to a lower overall survival regardless of treatment. Fogar looked at patients with pancreas and biliary tract tumors and found that patients with cancer had lower levels of circulating lymphocytes compared to healthy controls. Patients with less than 1.2 x 109/L circulating lymphocytes had shorter survival than those with values greater than 1.2 x 109/L (p<0.01). Another study showed that pancreas cancer patients with a lower neutrophil to lymphocyte ratio (NLR) had a median overall survival of 2.4 months compared to 7.7 months in patients with a normal NLR. A lower lymphocyte count has been associated with shorter survival times in patients with various other solid tumors including colorectal, non-small cell lung cancer, and ovarian cancer. Patients with low lymphocyte counts after treatment have also been shown to have shorter survival times. Campian and colleagues looked at patients with stage III non-small cell lung cancer. Eighty- nine percent of patients had normal total lymphocyte counts (defined as > 1,000 cells/mm3) prior to receiving standard therapy. Two months after starting treatment, a 67% overall reduction of total lymphocyte counts was seen, with a median of 500 cells/mm3. This occurred irrespective of the chemotherapy regimen given. Analysis showed a 70% higher rate of death related to lower total lymphocyte counts at 2 months compared with those with a count higher than 500 cells/mm3.

To date, no study has evaluated the role of targeted agents in different tumor types and their effect on lymphocyte numbers and outcomes. The purpose of our study will be to evaluate targeted agents as a single agent to determine if 1) there is a relationship with circulating lymphocytes and 2) if low lymphocyte counts related to treatment can be associated with outcome.

Requested Studies:

A multicenter, open-label, single-arm phase II study of safety and efficacy of a once three-weekly regimen of Herceptin monotherapy in patients with HER2-overexpressing metastatic breast cancer
Sponsor: Roche
Sponsor ID: WO16229

A Phase II, Single-Arm, Open-Label Study of Trastuzumab-Mcc-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer
Sponsor: Roche
Study ID: NCT00679211
Sponsor ID: TDM4374g

A Phase II, Single-arm, Open-label Study of Trastuzumab-MCC-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer Who Have Progressed While Receiving HER2-Directed Therapy
Sponsor: Roche
Study ID: NCT00509769
Sponsor ID: TDM4258g

BRIM 3: A Randomized, Open-Label, Controlled, Multicenter, Phase III Study in Previously Untreated Patients With Unresectable Stage IIIC or Stage IV Melanoma With V600E BRAF Mutation Receiving Vemurafenib (RO5185426) or Dacarbazine
Sponsor: Roche
Study ID: NCT01006980
Sponsor ID: NO25026

A Pivotal Phase II, Multicenter, Single-arm, Two-cohort Trial Evaluating the Efficacy and Safety of GDC-0449 in Patients With Advanced Basal Cell Carcinoma
Sponsor: Roche
Study ID: NCT00833417
Sponsor ID: SHH4476g

An International Multi-centre Open-label 2-arm Phase III Trial of Adjuvant Bevacizumab in “Triple Negative” Breast Cancer.
Sponsor: Roche
Study ID: NCT00528567
Sponsor ID: BO20289

Available – Avastin in Addition to Platinum-based Chemotherapy is Indicated for First-lime Treatment of Patients With Locally Advanced, Metastatic or Recurrent Non-small Lung Cancer Other Than Predominantly Squamous Cell Histology
Sponsor: Roche
Study ID: NCT02596958
Sponsor ID: ML21217

A Phase 1 Dose-Escalation Study of the Safety and Pharmacokinetics of GDC-0973/XL518 Administered Orally Daily to Subjects With Solid Tumors
Sponsor: Roche
Study ID: NCT00467779
Sponsor ID: MEK4592g

A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Efficacy and Safety of Vismodegib (GDC-0449) As Maintenance Therapy in Patients With Ovarian Cancer in a Second or Third Complete Remission
Sponsor: Roche
Study ID: NCT00739661
Sponsor ID: SHH4489g

A Phase II, Multicenter, Open-label, Three-cohort Trial Evaluating the Efficacy and Safety of Vismodegib (GDC-0449) in Operable Basal Cell Carcinoma (BCC)
Sponsor: Roche
Study ID: NCT01201915
Sponsor ID: SHH4812g

An Open-Label, Phase I Study of Systemic Hedgehog Pathway Antagonist, GDC-0449, in Patients With Locally Advanced or Metastatic Solid Tumors That Are Refractory to Standard Therapy or For Whom No Standard Therapy Exists
Sponsor: Roche
Study ID: NCT00607724
Sponsor ID: CDR0000585468