List of Clinical Research Projects

While usage of tobacco in any form is associated with higher risk of developing oral cancer, difference in the ability to metabolize these chemical carcinogens forms the basis of interindividual variability to develop cancer apart from the magnitude of exposure to the carcinogen. These chemical carcinogens require activation by Phase I metabolizing enzymes followed by detoxification via conjugation by Phase II enzymes. Polymorphisms in these xenobiotic metabolizing enzymes can lead to an increased risk of developing HNSCC. Hence the objective of the project is to investigate the role of genetic polymorphisms in the risk of developing HNSCC and to calculate the prevalence of these genetic polymorphisms (minor allele frequency) among the participants.

This proposed study seeks to investigate the effect of malnutrition on the pharmacokinetics of chemotherapy drugs among pediatric cancer patients in India. By assessing the influence of malnutrition on the serum metabolomic profile, important metabolites that are distinctly lowered or raised in the context of nutritional deprivation will be identified. A population pharmacokinetic model of chemotherapy drugs will be developed including these metabolites as covariates. This approach is expected to allow dose optimization of chemotherapy drugs based on the metabolomic profile of an individual suffering from malnutrition. Such optimization is crucial for mitigating the economic burden associated with chemotherapy-induced adverse events in pediatric oncology. Despite the multifactorial determinants of poor outcomes and reduced tolerability in malnourished pediatric patients undergoing chemotherapy, quantitative analysis of these factors is lacking in current literature. Hitherto no such effort has been used integrating pharmacokinetic, pharmacodynamic, and metabolomic approaches to devise individualized dosing strategies. Therefore, the ultimate goal of this study is to formulate guidelines or algoriths for chemotherapy drugs dosing in pediatric cancer patients, to be disseminated via a mobile/web application. Implementation of these adaptive dosing strategies has the potential to curtail hospitalization costs, minimize late effects, and ultimately enhance outcomes within this vulnerable population.

Sunitinib is an oral multi-targeted tyrosine kinase inhibitor approved for the first-line treatment of metastatic renal cell carcinoma (mRCC). Sunitinib has wide inter- and intra- individual variability in dose-concentration relationship due to its pharmacokinetic characteristics and genetic polymorphism. Moreover, it has drug-drug interactions that can profoundly alter/affect its plasma concentration. It has excellent exposure-efficacy relationship. A 10-fold difference in plasma exposure was found in mRCC patients who received the standard dose of sunitinib. Furthermore, it has a narrow therapeutic index and its treatment is often associated with severe toxicity, necessitating dose reductions or discontinuation. We found that therapeutic drug monitoring is routinely feasible and may both contribute to improve toxicity management and to identify sunitinib underexposure. So we plan to conduct a randomized study to see whether individualization of dose based on the sunitinib plasma levels would lead to better tolerability and improved efficacy in mRCC patients.

Over 55% of all malignancies occur in persons aged 65 years or older. Ageing brings about various physiological changes that can influence how cancer treatments work in the body and it underscores the need for tailored pharmacokinetic considerations in cancer treatment for older adults. Docetaxel has significant activity in solid malignancies, including breast, non-small cell lung, prostate, gastric and head and neck cancers. Despite its effectiveness, docetaxel is associated with several adverse effects. Management of side effects and the decision to use docetaxel, especially in older patients requires careful consideration and often involves premedication protocols to mitigate risks. Model-based dosing of chemotherapy agents throws light on patient-specific dosing, which tailors the dose of chemotherapeutic agents based on the unique characteristics of the patient. Population PK analysis has the potential to integrate all relevant PK information across a range of doses and populations to identify factors that can affect a drug’s exposure. These analyses, in turn, can inform strategies to select initial dosage regimens, manage dosing and administration for a given subpopulation, plan subsequent studies, or support labelling. Therefore, this study aims to create a popPK mathematical model for the dosing of Docetaxel tailored for the Indian elderly population.

The kidneys play a very important role in xenobiotic elimination. Renal function is known to decrease with advancing age. Renal function is reduced by ∼1% per year beyond 30–40 years of age, so that by age 70, renal function may have decreased by 40% owing to shrinkage in renal mass, age-related reduction in renal blood flow, and a gradual loss of functioning nephrons. Most anticancer agents have narrow therapeutic indices, and several of them are excreted renally. Therefore, accurate estimation of glomerular filtration rate (GFR) is extremely important for optimal dosing of anticancer drugs in the elderly. Plasma clearance of inulin, iohexal and iothalamate are considered precise markers for the calculation of GFR. These tests are limited by the need for continuous intravenous infusions, and repeat blood and urine collections causing inconvenience to patients, besides being expensive, cumbersome and time consuming. The 99mTc-DTPA is a reliable method to measure GFR. It also has many advantages such as its availability, lower cost and the option of performing renal imaging alongside quantifying GFR. The Cockcroft–Gault (CG) formula was published in the 1970s as a bedside equation for estimated creatinine clearance (eCrCl). However, this equation is an imprecise estimate of true GFR in large part due to its failure to adequately compensate for several non-GFR determinants of serum creatinine (SCr), such as body composition, diet, race, tubular secretion, and extrarenal elimination of creatinine. Improved methods for determining eGFR have been developed in the last 20 years, notably the modification of Diet in Renal Disease (MDRD) Study equation (MDRD-4 and MDRD-6) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the CKD-EPI Cystatin C equations. These equations were developed with standardized SCr values and iothalamate clearance as the reference, and they incorporate surrogates such as age, sex, and race to account for the effects of some non-GFR determinants of SCr. Recently, the Berlin Initiative Study (BIS) creatinine and Cystatin C equation, appears to offer better accuracy than either the MDRD or CKD-EPI equation. Cystatin C is considered more reliable than serum creatinine in the elderly population because it is not affected by changes in muscle mass. Although the use of these newer equations results in a value that is closer to the true GFR when compared to the CG formula and are considered a potential replacement for the same, their performance in geriatric cancer patients is still uncertain and has not yet been investigated. This study aimed to assess the most accurate GFR estimating equation in older Indian patients with cancer.

Cancer chemotherapy is often associated with the adverse events and many times this leads to interruption of the therapy or even discontinuation of the cancer chemotherapy. New approaches to improve tolerability and reduce adverse sequelae of cancer chemotherapy are urgently needed. One such approach is the combination of natural bioactive compounds with traditional chemotherapeutic drugs which can potentiate anti-cancer efficacy and reduce side-effects of chemotherapy. Docetaxel-based chemotherapy is commonly used for many solid cancers. The common side effects of Docetaxel are low white blood cell count and low red blood cell count, occurring in greater than 30% for patients taking Docetaxel. Based on the traditional literature of Guduchi (Tinospora cordifolia), its clinical usage experience, experimental studies related evidences and biological plausibility derivable from plant-attributes; Guduchi has the potential to countercheck the adverse events of cancer chemotherapy and complement in the overall cancer management. Most promising effects of Tinospora cordifolia demonstrated is immunomodulatory activity through increase in GM-CSF which leads to leukocytosis and improved neutrophil function. This study will help to determine whether the addition of a standardized water extract of Tinospora cordifolia, to docetaxel-based chemotherapy, will help reduce the adverse effects and improve Quality of Life (QoL). The study will be done in advanced/metastatic solid tumor commonly treated with Docetaxel based chemotherapy.

Radiation Therapy (RT) either alone or in combination with chemotherapy (chemoradiotherapy-CTRT) is one of the common treatments for various cancers. While RT/ CTRT remain a very effective treatment, there are side effects associated with them causing significant deterioration in quality of life. Recently a study from BARC has demonstrated the benefit of using chlorophyllin (CHL) tablets as an agent which can reduce the side effects associated with RT/ CTRT in certain cancers. A phase 1 clinical study in healthy volunteers indicated that CHL is safe and tolerable in humans and has not shown any severe adverse events. Our primary aim is to assess if CHL can reduce the toxicity of radiotherapy/ chemoradiotherapy in various cancers as well as understand the mechanism of chlorophyllin in terms of anti-inflammatory, stem-cell mediated tissue regeneration and chemokine profile.

Mucositis is a consequence of high dose chemotherapy that is administered to patients undergoing bone marrow transplant. Currently there are no universal protocols that have been accepted as a standard to prevent and treat oral mucositis in the transplant setting. A novel formulation has been developed in the form of lozenges, whose active ingredient is curcumin. Curcumin has demonstrated anti-inflammatory properties by inhibiting inflammatory cytokines through NF-κB suppression. Promising results from a pilot study have led to the initiation of a phase III randomized trial. The study aims to evaluate the efficacy of curcumin lozenges in reducing the incidence and duration of oral mucositis in autologous bone marrow transplant recipients.

I am the active member of the EORTC Quality of Life questionnaire Group (EORTC QLG) and involved in conducting multiple multi-national EORTC Quality of Life questionnaire development studies. These studies are in different stages of development, and we are collecting the relevant patients QoL data and submitting the same to the EORTC. Subsequently this data will be incorporated in the QoL questionnaires developed in the future. As a part of these questionnaire development, we contributed for the questionnaires developed in the Gastric, breast, pancreas, Renal, and head and neck cancers, pediatric cancers.

MSP008-22 is a novel molecule with anticancer effects demonstrated in in-vitro and in-vivo animal studies. Specifically, MSP008-22 has shown efficacy in the breast cancer and prostate cancer cell lines. Safety of MSP008-22 has been tested in in-vitro studies, preclinical single dose and repeat dose studies in animals, as well as safety pharmacology studies in animals and it was found to be safe up to the dose of 2000 mg/ kg body weight. Safety Pharmacology studies of MSP008-22 are completed for cardiovascular, respiratory, and central nervous systems and was found to be safe. The molecule did not exhibit the required level of cytotoxicity at any of tested concentration both in presence and absence of metabolic activation with 3-hour exposure and at also in the absence of metabolic activation with 22- hour exposure at and upto 424 µg/mL in in-vitro chromosomal aberration test performed using cultured human peripheral blood lymphocytes. The No Observable Effect Level (NOEL) for MSP008- 22 was 1000 mg/ kg body weight for Sprague Dawley rats. The current study “A single arm, open label, multi-centric, dose-ranging, single ascending dose, first-inhuman, phase I trial to assess safety, tolerability, and pharmacokinetic profile of MSP008- 22 in patients with Stage IV of advanced solid tumors (ovarian cancer, breast cancer including Triple-negative breast cancer, head and neck squamous cell cancer)”, is a First-in-Human trial with the primary objective to understand the safety and tolerability of the investigational medicinal product in humans and secondary objective being estimation of the pharmacokinetic profile of the MSP008-22 in humans after a single oral