Clinical trial of APCEDEN (Dendritic cell therapy) in refractory solid tumours..

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1 Clinical trial of APCEDEN (Dendritic cell therapy) in refractory solid tumours.. BACKGROUND: India sees about 1 million new cancer cases every year. Of these, one third die every year. It is projected that by the year 2025, there is going to be a fivefold increase in cancer cases in India, 2.8 fold increase due to tobacco and 2.2 fold increase due to ageing. Such a dramatic rise in cancer cases is more than double that predicted for developing countries like USA. Presently three percent of the population in India is suffering from one or the other type of cancer. In 2012, more than 5.55 lakh people have died due to cancer in India. In spite of good advancements for diagnosis and treatment, cancer is still a big threat to the mankind. The conventional treatment modalities like Surgery, Radiation and Chemotherapy carry morbidity and require a recoupment period after each dose. Immunotherapy has emerged as a safe treatment option in the last couple of years. Dendritic cell (DC) therapy in management of Cancer is regarded as the latest breakthrough in Immunotherapy. Various invitro and invivo scientific studies have shown that DC can be effectively used to activate the immune system against the cancer. This concept seems to be more viable option, as compared to any chemical entity directly targeting cancer cells because these modalities cannot discriminate between Cancer cells from healthy cells undergoing mitosis. In view of DCs potential in treatment of cancer backed by various preclinical models, clinicians evinced great interest in using them in a clinical setting. Human clinical trials are currently ongoing in several institutions against various cancers like breast, lung, myeloma, prostate and renal cells cancers. Sipuleucel-T was approved by the U.S. Food and Drug Administration (FDA) on April 29, 2010, to treat asymptomatic or minimally symptomatic metastatic HRPC i;ii. This therapy is also widely practiced in European countries as well. Simultaneously research is ongoing on to identify and understand which antigens or peptides are specifically associated with cancer and can be used in a Dendritic cell formulation. Since cancer cells exhibit tumor cell heterogeneity there is a need for preparation of cocktail of antigens for better targeting of Cancer cells. There was a need to further prove its safety tolerability and efficacy in clinical trial settings through properly designed and conducted clinical trials and simultaneously assess the immune responsiveness of such a therapy. The current Dendritic Cell formulation under investigation is being processed by APAC Biotech is derived from CD14+ blood monocytes in vitro and are completely autologous in origin. DCs are being derived from CD14+ blood monocytes, by culture with granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4). These dendritic cells are exposed to the patient s own autologous tumor tissue so that the antigen specific dendritic cells are produced that target the specific tumor the patient is suffering from. Mature DCs were harvested on Day 8 and checked for surface markers (CD 80 + (PE)CD 86+ (APC) and CD 83+( FITC) positive) and adequate counts ( > 1 million DCs) per dose. These are not derived from CD34+ bone marrow cells or mesenchymal stem cells.

2 The Oncologists fraternity in India expressed great interest in conducting a well designed proof of concept/phase II Clinical trial with DCT (Dendritic Cell Therapy) processed by APAC Biotech, Gurgaon. The objective of the study was primarily for academic interest and scientific pursuit. The goal was to study the safety, efficacy and tolerability in patients with refractory solid malignancies. This clinical trial was therefore initiated in the general interest of Cancer patients at large. MATERIAL AND METHODS: Study Details: The study entitled An open label, multi-centre, non-randomized, single arm study to evaluate the safety and efficacy of Apceden *Dendritic Cell (DC) immunotherapy+ in patients with refractory solid malignancies, on symptomatic treatment was conducted across 6 sites in India. The details of the sites where the study was conducted have been tabulated below: Table1: CLINICAL INVESTIGATORS Dr. Bharath Rangarajan, Narayana Hrudayalaya Hospitals, BANGALORE Dr. Shyam Aggrawal Sir Gangaram Hospital, NEW DELHI Dr. S Subramanian VS Hospital, CHENNAI Dr. Minish Jain Ruby Hall Clinic PUNE Dr. Suresh Attili Bibi General Hospital HYDERABAD Dr. Senthil Rajappa Basavatarakam Indo-American Cancer Research Institute, HYDERABAD The study screened 65 cases, of which 51 received at least one dose. All these patients were evaluable for safety. 38 patients formed the Intention to Treat (ITT) population. These were the patients who received at least one dose and underwent one response evaluation visit. 12 patients completed all study visits and formed the completers population. The study started patient accrual in the month of September 2011 and concluded accrual in March The last patient last visit was September 2012.Total duration of the study was about 18 months, which included 6 months of recruitment and about 4 months of treatment and 3 months of post treatment follow-up and 2 months each of pre and post-study period at the site. All patients signed informed consent, the study was approved by the respective Institutional Ethics Committees and the trial was registered with Clinical Trial Registry India. The global and national standards of ethical conduct of the study were adhered to. ICH GCP (E6), Indian Good Clinical Practices Guidelines and ICMR Ethical Guidelines for Biomedical Research on Human Subjects were followed. The trial was registered in CTRI (Clinical trial registry of India), CTRI/ 2011/07/ Subject Selection Criteria Inclusion Criteria

3 Subjects met the following criteria to be included in the study. 1. Male and female subjects from 18 to 70 years of age 2. Histologically confirmed refractory solid tumors on symptomatic care 3. Available tumor tissue 4. (Note: Fresh tissue sample (if possible) was the first preference along with Formalin Fixed Paraffin Embedded tissue and/or unstained slides if available. These samples were collected and shipped separately with cool gel packs in package in order to maintain 4-80 C during transport and reach APAC lab within 24 hours of collection) 5. Life expectancy at least 3 months 6. ECOG status < 2 7. Adequate Organ function: A. Liver function: i. In the absence of disease involvement in the liver and if bilirubin 1.5 times institutional upper limit of normal (ULN), AST (SGOT), ALT (SGPT) and GGT may be 2 times ULN ii. In the presence of disease involvement in the liver and if bilirubin 1.5 times institutional upper limit of normal (ULN), AST (SGOT), ALT (SGPT) and GGT may be 5 times ULN iii. Alkaline phosphatase 2.5 times ULN iv. Albumin 3.0 g/dl B. Renal function: i. Serum creatinine 1.5 times ULN ii. No active acute or chronic urinary tract infection iii. Urinalysis with no evidence of proteinuria C. Hematology Status: i. Platelet count 100,000 platelet/cumm ( /L) ii. Hemoglobin 9 g/dl. D. WBC 3,000/cumm E. Coagulation Profile: i. Acceptable coagulation profile (PT or INR, PTT) < 1.5 times ULN 1. Serum immune-globulins IgA and IgM within normal range 2. No blood transfusion within 4 weeks of joining the study. 3. No exposure to immunotherapy and cancer Immunotherapy 4. Females of child bearing potential must have negative urine pregnancy test at screening 5. Child bearing potential participants to exercise effective birth control measures 6. Able to provide written, voluntary informed consent, comply with trial procedures, and have accessibility to the site. Exclusion Criteria Subjects meeting the following criteria were not enrolled: 1. Chemotherapy, antibody therapy, major surgery or irradiation within 4 weeks of study enrolment 2. Exposure to any investigational agent within 30 days of the Screening Visit. 3. Central Nervous System Metastases

4 4. Known Autoimmune disease or disease process that involves the use of immunosuppressive therapy 5. Patients on long-term (more than one week) steroid therapy within 4 weeks of study entry 6. Underlying Cardiac disease associated with (NYHA) New York Heart Association Class III and IV (Appendix 11) function or unstable angina related to atherosclerotic cardiovascular disease 7. Active infection or other active medical condition that could be eminently life threatening, including no active blood clotting or bleeding diathesis 8. Known HIV infection 9. Active Hepatitis 10. Active Tuberculosis 11. Any Uncontrolled active, infection. 12. Substance abuse or any condition that might interfere with the subject s participation in the study or in the evaluation of the study results. 13. History of hypersensitivity to Immunotherapy such as asthma, anaphylaxis or other severe reactions 14. Any medical, psychological, sociological or geographical constraints judged by the investigator that would impede patient s compliance to the study procedures. Study Design: This was a multi-centric, single arm, open-label, non- randomised study. The detailed study schema in the figure below: Figure 1: Eligible patients underwent apheresis for collection of Peripheral Blood Monocytes/Mononuclear Cells (PBMCs). These cells were cultured and processed to differentiate into mature dendritic cells (DCs) against their specific tumor antigens. These mature DCs were harvested on Day 8. The harvested DCs were divided into 6 aliquots of 15ml each. 6 doses of DC vaccine were administered over 14 weeks period: Day 9, Day 23, Day 37, Day 58, Day 79 and Day 100, The post-treatment follow-up were two and six weeks apart. Safety assessments were done at all visits and response assessment was done at Day 58, Day 100 and Day 184 or End of Study visit. Study Objectives:

5 Primary Objectives were to determine the safety and tolerability of the Apceden in patients with refractory solid malignancies on symptomatic treatment and the efficacy by determining tumor response by (a) immune-related criteria response (irrc) iii and (b) RECIST criteria. Secondary Objectives were to assess Quality of Life (QOL) as measured by the FACT-G (Functional Assessment of Cancer Therapy-General), change in immune response by measuring immune parameters pre and post therapy by flowcytometry in peripheral blood like; CD4+ and CD8+ count, activity of Natural Killer Cells and IFN-Gamma. Computation of Time to Treatment Progression (TTP) was also one of the secondary objectives. Time to Treatment Progression (TTP) was defined as the time interval from the date of enrolment to the date when progression of disease was first documented. Patient Population: Both male and female patients with recurrent solid malignancies on symptomatic care, with at least 3 months of life expectancy, available tumor tissue, ECOG of < 2, having adequate organ function and blood counts were enrolled. Pregnant females were excluded from participation. Standards for Efficacy and Safety Assessments: Primary Endpoints were safety and tolerability as measured by the incidence and severity of treatmentemergent adverse events and incidence of serious adverse events. Efficacy of therapy as measured by Tumor Response and Objective Response assessment as per RECIST (version 1.1) and irrc (immune related response criteria). The Objective Response Rate (ORR) as per protocol, included the percentage of patients who showed Complete Remission (CR), Partial Remission (PR) and Stable Disease (SD). Secondary Endpoints were to assess Quality of Life (QOL) as measured by the FACT-G (Functional Assessment of Cancer Therapy-General); change in immune response by measuring immune parameters pre and post therapy by flowcytometry and time to treatment progression. Safety and tolerability secondary endpoints were also measured by the shift from baseline in ECG, Echo, vital signs, clinical laboratory parameters, ECOG (PS) and use of concomitant medications. Safety events were graded by using revised National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0 (published 28 May 2009). All Safety events were coded using MedDRA (version 13) Statistical Analysis was done using SAS package (SAS Institute Inc., USA, and Version 9.1.3). A detailed statistical analysis plan (SAP) was prepared prior to locking the database and performing the final analysis for the study. RESULTS: Demographics and Patient Characteristics: 51 cases were enrolled and dosed in the trial. demographic is tabulated in the table below: The subject Table 2: Table 1: Demographic and Baseline Characteristics

6 Safety Population N=51 Parameter Category/Statistic All Subjects Gender, n (%) Male 24 (47.1%) Female 27 (52.9%) Prior Cancer Treatment, n (%) Chemotherapy 45 (88.2%) Radiation 20 (39.2%) Surgery 20 (39.2%) Tumor Tissue Collection, n (%) Paraffin Block 26 (50.9%) Unstained Slides 2 (3.9%) Paraffin Block and Tissue 9 (17.6%) Other (biopsy) 14 (27.4%) Age (yr) Mean 52.9 SD Minimum 28 Median 55.0 Maximum 72 Graph 1: The cancer types that were recruited are summarized in the chart below: The maximum number ca-ovary cases were enrolled, followed by colon cancer and head and neck cancers. Most cases had refractory disease with multiple chemotherapy failures and metastatic disease. There were on-going comorbid conditions like hypertension, diabetes, chronic obstructive pulmonary disease and coronary artery disease which were under control with medications. Primary Objective Results: Safety and tolerability: All 51 cases were evaluated for safety. In all 225 infusions were administered and all were well tolerated barring only one instance of chills and rigors associated with mild pyrexia reported during a single infusion. The patient continued on the study, symptoms were resolved and did not reappear during subsequent infusions. According to investigator it could have been possibly related to study therapy. AEs were reported in 29 patients (56.9%) irrespective of causal relationship to study therapy. 41 AEs were Treatment Emergent AEs (TEAEs). TEAEs comprised of all adverse symptoms that started and /or worsened after start of study therapy and during the course of the study. These TEAEs, as per investigator judgement were associated with the primary cancer of the patients and not related to study therapy. 12 out of 51 cases

7 (23.5%) had AEs that were categorised as Treatment Related Adverse Events (TRAEs). These included AEs that were classified by investigator as unlikely, possibly, probably or definitely related to study treatment. According to investigator all TRAEs reported were unlikely to be due to study therapy. Only one among the TRAEs; chills and rigors was adjudged as possibly related to study therapy by the investigator. 21.6% of the patients reported serious adverse events (SAEs). None of the SAEs were related to study therapy. All were attributed to the primary cancer condition and associated metastases and not adjudged related to study therapy. 13 (25.4%) patients died while on study. All the deaths were due to disease progression and unlikely to be related to study therapy. Efficacy: Response Rates: 11 out of 38 (28.9%) evaluable cases (ITT) showed Objective Response (OR) at Day 184/End of Study visit as per RECIST version (1.1). 16 out of 38 (42.1%) showed OR by Immune Related Response Criteria (irrc) at Day 184 /End of Study. 9 out of 12 (75%) patients who completed (COMPLETERS) the study continued to show OR by RECIST (version 1.1) as well as irrc. One patient showed PR (Partial Remission) through-out the study among the reported OR cases. Best overall response was recorded for 43 cases. 11 of 43 (25.6%) cases showed objective response. Graph 2: Percentage of Patients showing Tumor Response (RECIST) in ITT Population: Graph 3: Percentage of Patients showing Tumor Response (irrc) in ITT Population:

8 Secondary Objective Results: Quality of Life (FACT-G): Results showed deterioration of QoL in 33.3 % of the patients from Visit 1 to Visit 3 and further deterioration in 55.6% of the patients from Visit 1 to Visit 6 after 3 cycles. But subsequently, there was an improvement in 61.1% patients from Visit 3 to Visit 8 after completion of 5 cycles indicating therapeutic benefit contributing in improvement of the general condition and stabilisation of disease of the patients towards end of therapy. Graph 4: Immune Response: Post vaccination sample of only 20 cases could be collected, so any meaningful inference could not be drawn for the endpoint due to lack of sufficient data. Time to treatment Progression (TTP): For ITT population who progressed the median TTP was computed to be 67.5 and 75 days by RECIST and irrc respectively. For ITT population 11 patients did not show disease progression as per RECIST and 16 patients continued to show OR at the last study visit as per irrc.

9 For Completers population who progressed the median TTP was computed to be 71 and 110 days by RECIST and irrc respectively. For Completers population 9 patients did not progress as per RECIST and irrc both criterion. Median Time to Treatment progression by both criterion was well above 9 weeks for both ITT and completers population. Although it was not part of the statistical analysis plan TTP was also calculated for the 38 cases found evaluable. The TTP of group showing Progression of Disease (PD) was compared with that of the group showing Objective Response (OR). The value of TTP was numerically higher in the Cohort showing OR as compared to PD Cohort and mean TTP for all evaluable cases. This indicates that patients in the OR group showed statistically significant delay in onset of progression of disease. The cut-off time for the patients who did not progress was kept as Dec 5 th Survival Analysis: Though not planned in the protocol, the median survival was computed for three cohorts in the study. As of Dec 5 th 2012, median survival for all subjects was calculated to be 173 days (N=38) and 123 days for those showing PD (N=13) and 55 days for non evaluable cases (N=13). For the group showing OR (N=25) more than 50% of the patients are still living so median survival cannot be calculated for this cohort. Graph 5 Conclusions: Studies with DC therapy show survival benefit. The provenge study reported a survival advantage 4.1 months over placebo. In a Phase 2 study, treatment with AGS-003 (DC Immunotherapy developed by Argos Therapeutics Inc.) iv ; v was associated with encouraging median and long-term survival for

10 newly diagnosed metastatic renal cell carcinoma (mrcc) patients; who presented with intermediate or poor risk factors. Adding AGS-003 to standard sunitinib doubled overall survival for these patients compared to historical results for such patients treated with sunitinib alone. Importantly, more than 50 percent of patients in the study survived longer than 30 months after initiating therapy, which is four times the expected rate for sunitinib, suggesting a pronounced survival benefit for the combination regimen with no added toxicity. In this study, it has been observed that survival results are good; overall median survival of 173 days. Median Time to Treatment Progression (TTP) in both ITT and Completers population was computed to be greater than 9 weeks and at the time of study conclusion 9 patients had not progressed and were continuing to show Objective Response. In this clinical trial, only patients with advanced and recurrent disease were treated. Considering the patient population; the results pertaining to safety, efficacy, tolerability, quality of life benefit and survival have been encouraging. The current clinical experience with Apceden TM has established the safety and efficacy of the therapy to a considerable extent. Immune parameters results however, could not be adequately concluded because of insufficient data. This data will help to plan for future studies in an appropriate clinical setting, with the right patient population and appropriate surrogate marker analysis for response and survival. Minimal residual disease may be the optimal clinical setting to apply for such a safe therapeutic approach and its use in combination with other therapeutic modalities may be an area to explore. Several other aspects of vaccine optimization, use of recombinant proteins for antigen preparation and method of application could be the points to be considered for future research. Reference List (1) Nandakumar A. National Cancer Registry Programme,Indian Council of Medical Research, Consolidated report of the population based cancer registries. New Delhi: Indian Council of Medical Research; (2) Sifferlin A. How Chemotherapy May Trigger Tumors' Resistance. TIME Ref Type: Magazine Article (3) Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med 1973 May 1;137(5): (4) Bhargava A, Mishra D, Banerjee S, Mishra PK. Dendritic cell engineering for tumor immunotherapy: from biology to clinical translation. Immunotherapy 2012 Jul;4(7): (5) Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, Taidi B, et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med 1996 Jan;2(1):52-8. (6) Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 1998 Mar;4(3):

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12 ii "Approval Letter - Provenge". Food and Drug Administration ml iii Jedd D. Wolchok, et al Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria. Clin Cancer Res 2009;15(23), iv Heng et al. International mrcc Consortium Database; November 2011 v Motzer et al. 10th International Kidney Cancer Symposium. Poster presentation. October 14, 2011