Status: New
| Name & address of the Laboratory/Organization | Tata Memorial Centre | |
| Website address | https://tmc.gov.in | |
| Affiliated to which Department/Ministry | Department Of Atomic Energy (DAE) | |
| CSR Registration Number | CSR00001287 | |
| Registration under 12A | 12A Registration no. - INS/12128 Provisional approval no.- AAATT3620RE20214 | |
| Registration under 80G | DIT(E)/ITO(Tech)/80G/2010-11 Provisional approval no.- AAATT3620RF20241 | |
| Name of the CSR Nodal | Dr Heena Shaikh | |
| Contact information of CSR Nodal | Phone- +91-22 -68735000 Extn: 5483, hshaikh@actrec.gov.in | |
| Principal Investigator | Dr Nandini Menon, hshaikh@actrec.gov.in | |
| Co- Principal Investigator (Co-PI) | ||
| Objective on the basis of need | Need for effective therapy in locally advanced resectable esophageal squamous carcinoma: • Locally advanced esophageal carcinoma is an aggressive. Despite use of multi-modality treatment, there is still an unmet need to improve long-term survival. Immune checkpoint inhibitors (ICIs, also known as immunotherapy) have shown improvement in pathological response rates when used in the neoadjuvant/peri-operative setting in resectable oesophageal cancer. Most of these have evaluated the role of ICI in resectable adenocarcinoma of the esophagus (more prevalent in the developed world) , with few studies evaluating it in esophageal squamous cell carcinoma (SCC). • The access to ICIs (immunotherapy) in LMICs (low- and middle-income countries) is limited due to its cost. Objective: To evaluate if triplet neoadjuvant chemotherapy with low-dose immunotherapy prolongs event-free survival compared to triplet neoadjuvant chemotherapy alone in patients with locally advanced resectable esophageal squamous carcinoma. The primary objective is to evaluate efficacy of low dose immunotherapy in combination with neoadjuvant chemotherapy in this setting. |
| Executive summary of the proposed project (In 250 words) | Locally advanced esophageal SCC is an aggressive cancer. Patients with locally advanced esophageal SCC suitable for surgery, are treated with chemotherapy given prior to surgery (neoadjuvant chemotherapy) followed by surgery. Despite this, outcomes are dismal with a recurrence rate of nearly 40% at 3 years. To improve outcomes, many trials around the world incorporate immunotherapy along with neoadjuvant chemotherapy. The huge cost of immunotherapy makes it out of reach of most India patients. We are proposing the use of low-dose immunotherapy along with neoadjuvant chemotherapy in these patients to reduce recurrence rates and prolong survival. We have developed a model of low dose immunotherapy, which costs a fraction of the cost of regular dose of immunotherapy. Study Design & Population: Randomized controlled, open-label, phase III superiority study that will include patients with locally advanced resectable esophageal SCC planned for curative intent treatment. Sample Size: The total sample size for the study is 362 patients (345 patients + 5% to accommodate for attrition). Outcomes • Primary Endpoint: 3-year event-free survival (EFS). • Secondary endpoints: Overall Survival (OS), Objective Response Rate (ORR), R0 resection rates, pathological responses, patterns of treatment failure, Quality of Life (QOL), Safety. • Tertiary Objectives: Exploring biomarkers Study Interventions: Arm -A: Neoadjuvant (pre-operative) chemotherapy followed by surgery Arm-B: Neoadjuvant (pre-operative) chemotherapy with low dose Nivolumab (immunotherapy) followed by surgery. The dose of Nivolumab is 40 mg IV every 3 weeks. Chemotherapy in both arms will be Docetaxel + Cisplatin/Carboplatin + 5-FU/Capecitabine Study duration: 9 years (6 years of accrual and 3 years of follow up) |
| Technology Readiness Level (If not a new project but an advancement of existing know how) | The concept of using a low dose of immune checkpoint inhibitors is a relatively new concept with good evidence to support it. A phase 3 randomized trial of showed that low dose Nivolumab in combination with triple metronomic chemotherapy improved survival in recurrent /metastatic head neck squamous carcinoma (R/M HNSCC). This evidence has been published and being widely used across for R/M HNSCC. Low dose of immunotherapy is being evaluated across various cancers and various settings such as advanced esophageal, lung cancer, colorectal cancer and in resectable head and neck cancers. Immunotherapy in combination with chemotherapy is also widely used in esophageal cancer and other cancers. Approximately 70%-75% of the PD-1 receptors on T cell required to be occupied for its activation. Nivolumab is an anti–PD-1 monoclonal antibody, 70% of PD-1 receptor occupancy is achieved by nivolumab at a dose of 0.3 mg/kg (single dose), and hence, there is a theoretical possibility of benefit with this dose. In phase 1 studies of Nivolumab, similar levels of clinical activity were observed at all doses studied, starting from 0.1mg/kg; PD-1 receptors on T cells were occupied equally at doses in the 1-10 mg/kg range. Based on this phase 1 trial data we have selected the low dose for this study. Nivolumab is available in India for use. Medical oncologists have experience in administration of Nivolumab and management of its toxicities. |
| Outomes or Deliverables | The main outcome being evaluated in this study is the efficacy of low dose immunotherapy (Nivolumab) in combination with neoadjuvant (pre-operative) chemotherapy in the esophageal SCC. The primary efficacy variable (primary endpoint) is the 3-year.Event Free Survival (EFS) rate. The other efficacy variables are overall Survival (OS) and objective response rate (ORR) (secondary endpoints). EFS is be defined as the time period from the date of randomization till the occurrence of any event such as disease progression/recurrence, treatment discontinuation or death due to any cause. The other secondary endpoints include treatment safety, R0 resection rates, peri- and post-operative complication rates, pathological response rates, and quality of life (QOL). |
| Project aligned with which most relevant UN SDGs | Goal 3 - Good Health & Well-Being |
| Duration (In years) | 6 years for patient accrual and 3 years follow up. |
| Expected Impact | The expected impact is improved access to immunotherapy in the setting of resectable esophageal SCC. Reduction of cost of immunotherapy (Nivolumab) to one-fifth of the standard dose will improve access by: 1) making the drug more affordable 2) Bringing the overall cost of pre-operative chemo-immunotherapy within the limits of financial support/ insurance cover of various government health schemes. Patients can then avail the benefit of immunotherapy without burdening the health care system and avoid out of pocket expenditure. This will also benefit other low- and middle-income countries across the world where access to immunotherapy is limited. |
| Implementation model (self- implemented/ outsourced partnership) | Self-implemented |
| Total Budget (Recurring +Non-Recurring Expenses) | Total Budget = 96,779,677 INR Non-recurring= 86,162,000 INR (including cost of Nivolumab 40 mg = 27,512,000 INR) Recurring= 10,617,677 INR |