A Post marketing surveillance study evaluating safety and efficacy of APCEDEN®, an autologous dendritic cell immunotherapy, when administered according to the prescribing information in India (APASS)

Name of MAH:

APAC Biotech Pvt. Ltd.

|Title:

A Post marketing surveillance study evaluating safety and efficacy of APCEDEN®, an autologous dendritic cell immunotherapy, when administered according to the prescribing information in India (APASS)

|Rationale:

APCEDEN® is an autologous dendritic cell based cellular immunotherapy product provisionally approved to be used in patients with refractory prostate, colorectal, ovarian or lung cancer. This is the first of its kind product approved in India, and therefore this study is proposed to investigate the short term and long term safety aspect of this product when used as per the prescribing information.

|Phase:

Post marketing surveillance study

|Study Period:

Sep 2017 –July 2019

|Number of patients:

Prostate cancer – 50

Ovarian cancer - 50

Colorectal cancer- 50

Lung cancer- 50

|Study design:

Open-label, multi-centre, safety and efficacy study

|Centres:

All centres across India, which are eligible to use APCEDEN®

|Indication:

Prostate cancer, Ovarian cancer, Colo-rectal cancer and Lung cancer

|Treatment:

The treatment regimen and the process of APCEDEN® manufacture starts with aphaeresis of the patient. The peripheral blood mononuclear cells (PBMCs) obtained trough aphaeresis serve as the starting substance for manufacturing, on the 8th day of the aphaeresis the immunotherapy (APCEDEN®) is ready and supplied to the physician. Patients to receive 6 doses of APCEDEN® in total. Each dose (0.5 ml ID. and 100 ml IV) at an interval of 15 days.

|Primary safety outcome:

·       Overall Survival [Time Frame: From date of subject inclusion to date of death or assessed up to 198 days for ovarian cancer; 87 days for colo-rectal cancer; 184 days for lung cancer; 356 days for prostate cancer]

·       Evaluation of objective response through Immune related Response Criteria (irRC): measure of PD; PR and SD.

·         Immune response as assessed through Treg population and serum IFN-γ levels

·       Monitor treatment emergent adverse events. Safety as assessed by percentage of patients with any Adverse Event (AE), AE leading to Study Drug Discontinuation, AE leading to death, Serious Adverse Event (SAE), AE related to study drug, SAE related to study drug (Time Frame: Every 15 days following first dose for up to 117 days).

|Secondary outcome:

·       Quality of life as assessed by the Functional Assessment of Cancer Therapy-General (FACT-G)

·       Evaluation of tumour response as per RECIST. Monitor for evidence of the following tumor responses: Overall response rate (ORR), time to progression (TPP); Progression free survival (PFS) and Disease free survival (DFS)

·       To explore the correlation between APCEDEN® immune response and overall survival. (Time Frame: Baseline to study completion)

|AE of interest

·       Chills, rigour, mild fever, infusion site itching and fatigue

Inclusion and Exclusion criteria:

|Prostate Cancer

|Inclusion Criteria

Exclusion criteria

|· Able and willing to give written informed consent

· Age: 18 -75 years

· Patients with a histologically confirmed diagnosis of prostate cancer.

· As per the physician the cancer should be refractory to at least 2/3 prior therapies, with measurable disease.

· Hormone refractory prostate cancer (HRPC); progressive disease despite androgen deprivation and serum testosterone <50ng/dL; progression defined as either:

1.    Rising PSA over 6 months with at least a 50% increase between the 1st and 3rd measurement, and the 3rd measurement >2.0 ng/ml; or

2.    Progression of metastatic lesion on bone scan, or

3.    Progression of lymph node metastasis by CT scan.

· Zubrod/WHO or ECOG performance status of 0-1. Life expectancy greater than 3 months

· Patient to have adequate venous access(to undergo leukapheresis)

· No known hypersensitivity to APCEDEN® or any of its constituents.

· Three or fewer bone metastases on a bone scan with minimal symptoms.

· No lymph node lesions greater than 3.0 cm at longest diameter.

· Adequate hematological, hepatic and renal function.

· Normal organ function and normal hematological parameters; laboratory parameters should be within normal range, except following laboratory parameters: HEMOGLOBIN ≥ 10 G/DL; GRANULOCYTES ≥ 1,500/µL; LYMPHOCYTES ≥ 1000/µL; PLATELETS ≥ 100,000/µL; SERUM CREATININ ≤ 2.0 MG/DL; SERUM BILIRUBIN ≤ 2.0 MG/DL; AST AND ALT ≤ 2 X THE NORMAL UPPER LIMITS; LDH ≤ 1,5X NORMAL UPPER LIMIT; CRP ≤ 1,5X NORMAL UPPER LIMIT; PROTHROMBIN TIME (PT) INTERNATIONAL NORMALIZED RATIO (INR) AND PARTIAL THROMBOPLASTIN TIME (PTT) WITHIN NORMAL LIMITS

· No prior history of a serious autoimmune disorder

· No concomitant medication with immune suppressive drugs

· No brain metastases leptomeningeal involvement (other than astrocytomas)

· No clinically significant pleural effusion

· No complete tumor obstruction (e.g., bronchus, ureter, or bowel)

· Patient should not be taking concurrent corticosteroids as these may subside the immune function and interfere with immunotherapy response.

· Patient should be able to adhere to the study visit schedule and other protocol requirements.

 Â·         History of other active malignancy.

·         Prior chemotherapy, radiation therapy, immunosuppressive or investigational therapy for metastatic disease in previous 12 months.

·         Strong opioids, immunosuppressives, megestrol acetate or other estrogenic hormones within 1 month prior to enrollment.

·         Brain, liver, or lung metastases; uncontrolled heart, liver, lung, or renal diseases or other serious illness.

·         Prior splenectomy.

·         History of moderate to severe lower limb lymphedema, or recent signs of deep venous thrombosis (DVT) or thrombo-embolic disease, or impending stroke.

·         History of immunodeficiency or autoimmune disease; positive HIV, HbsAg or anti-HCV.

·         Impending untreated spinal cord compression or urinary outlet obstruction.

·         Any medication that might affect immune function. (Exceptions: Nonprescription doses of NSAIDS; acetaminophen or aspirin; low doses of antihistamine therapy; normal range doses of vitamins; and H2 blockers).

   |Ovarian cancer

|Inclusion criteria

Exclusion criteria

|· Able and willing to give written informed consent

· Age: 18 to 75 years

· Patients with a histologically confirmed diagnosis of ovarian cancer.

· As per the physician the cancer should be refractory to at least 2/3 prior therapies, with measurable disease.

· Karnofsky status ≥ 70% and/or WHO/ECOG (Eastern Cooperative Oncology Group) performance status 0-2

· Life expectancy ≥ 3 months

· Patient to have adequate venous access(to undergo leukapheresis)

· No known hypersensitivity to APCEDEN® or any of its constituents.

· Three or fewer bone metastases on a bone scan with minimal symptoms.

· No lymph node lesions greater than 3.0 cm at longest diameter.

· Adequate hematological, hepatic and renal function.

· Normal organ function and normal hematological parameters; laboratory parameters should be within normal range, except following laboratory parameters: HEMOGLOBIN ≥ 10 G/DL; GRANULOCYTES ≥ 1,500/µL; LYMPHOCYTES ≥ 1000/µL; PLATELETS ≥ 100,000/µL; SERUM CREATININ ≤ 2.0 MG/DL; SERUM BILIRUBIN ≤ 2.0 MG/DL; AST AND ALT ≤ 2 X THE NORMAL UPPER LIMITS; LDH ≤ 1,5X NORMAL UPPER LIMIT; CRP ≤ 1,5X NORMAL UPPER LIMIT; PROTHROMBIN TIME (PT) INTERNATIONAL NORMALIZED RATIO (INR) AND PARTIAL THROMBOPLASTIN TIME (PTT) WITHIN NORMAL LIMITS

· No prior history of a serious autoimmune disorder

· No concomitant medication with immune suppressive drugs

· No brain metastases leptomeningeal involvement (other than astrocytomas)

· No clinically significant pleural effusion

· No complete tumor obstruction (e.g., bronchus, ureter, or bowel)

· Patient should not be taking concurrent corticosteroids as these may subside the immune function and interfere with immunotherapy response.

· Patient should be able to adhere to the study visit schedule and other protocol requirements

·      Pregnant or lactating women.

·      Known positive for hepatitis B or C or HIV.

·      Underlying cardiac disease associated with myocardial dysfunction that requires active medical treatment, or unstable angina related to atherosclerotic cardiovascular disease, or under treatment for arterial or venous peripheral vascular disease

·      Diagnosis of any other invasive cancer which is considered to be life-threatening within the next five years, and/or taking anti-cancer therapy for cancer other than ovarian (such as continuation of hormonal therapy for breast cancer diagnosed more than five years earlier).

·      Active infection or other active medical condition that could be eminently life-threatening, including active blood clotting or bleeding diathesis.

·      Brain, liver, or lung metastases; uncontrolled heart, liver, lung, or renal diseases or other serious illness.

·      Prior splenectomy.

·      History of moderate to severe lower limb lymphedema, or recent signs of deep venous thrombosis (DVT) or thrombo-embolic disease, or impending stroke.

·      History of immunodeficiency or autoimmune disease; positive HIV, HbsAg or anti-HCV.

·      Known autoimmune disease, immunodeficiency, or disease process that involves the use of immunosuppressive therapy.

|Lung cancer

|Inclusion criteria

Exclusion criteria

|· Able and willing to give written informed consent

· Age: 18 to 75 years

· Patients with a histologically confirmed metastatic adenocarcinoma of the lung

· .As per the physician the cancer should be refractory to at least 2/3 prior therapies, with measurable disease.

· Karnofsky status ≥ 70% and/or WHO/ECOG (Eastern Cooperative Oncology Group) performance status 0-2

· Life expectancy ≥ 3 months

· Patient to have adequate venous access(to undergo leukapheresis)

· No known hypersensitivity to APCEDEN® or any of its constituents.

· Three or fewer bone metastases on a bone scan with minimal symptoms.

· No lymph node lesions greater than 3.0 cm at longest diameter.

· Adequate hematological, hepatic and renal function.

· Normal organ function and normal hematological parameters; laboratory parameters should be within normal range, except following laboratory parameters: HEMOGLOBIN ≥ 10 G/DL; GRANULOCYTES ≥ 1,500/µL; LYMPHOCYTES ≥ 1000/µL; PLATELETS ≥ 100,000/µL; SERUM CREATININ ≤ 2.0 MG/DL; SERUM BILIRUBIN ≤ 2.0 MG/DL; AST AND ALT ≤ 2 X THE NORMAL UPPER LIMITS; LDH ≤ 1,5X NORMAL UPPER LIMIT; CRP ≤ 1,5X NORMAL UPPER LIMIT; PROTHROMBIN TIME (PT) INTERNATIONAL NORMALIZED RATIO (INR) AND PARTIAL THROMBOPLASTIN TIME (PTT) WITHIN NORMAL LIMITS

· No brain metastases leptomeningeal involvement (other than astrocytomas)

· No complete tumor obstruction (e.g., bronchus, ureter, or bowel)

· Patient should not be taking concurrent corticosteroids as these may subside the immune function and interfere with immunotherapy response.

· Patient should be able to adhere to the study visit schedule and other protocol requirements

·      Known positive for hepatitis B or C or HIV.

·      Underlying cardiac disease associated with myocardial dysfunction that requires active medical treatment, or unstable angina related to atherosclerotic cardiovascular disease, or under treatment for arterial or venous peripheral vascular disease

·      Diagnosis of any other invasive cancer which is considered to be life-threatening within the next five years, and/or taking anti-cancer therapy for cancer other than lung cancer (such as continuation of hormonal therapy for breast cancer or prostate cancer diagnosed more than five years earlier).

·      Active infection or other active medical condition that could be eminently life-threatening, including active blood clotting or bleeding diathesis.

·      Pregnant or lactating women.

·      Brain, liver, or lung metastases; uncontrolled heart, liver, lung, or renal diseases or other serious illness.

·      Prior splenectomy.

·      History of moderate to severe lower limb lymphedema, or recent signs of deep venous thrombosis (DVT) or thrombo-embolic disease, or impending stroke.

·      History of immunodeficiency or autoimmune disease; positive HIV, HbsAg or anti-HCV.

·      Known autoimmune disease, immunodeficiency, or disease process that involves the use of immunosuppressive therapy.

|Colorectal cancer

|Inclusion criteria

Exclusion criteria

|· Able and willing to give written informed consent

· Age: 18 to 75 years

· Patients with a histologically confirmed colorectal carcinoma

· .As per the physician the cancer should be refractory to at least 2/3 prior therapies, with measurable disease.

· Karnofsky status ≥ 70% and/or WHO/ECOG (Eastern Cooperative Oncology Group) performance status 0-2

· Life expectancy ≥ 3 months

· Patient to have adequate venous access(to undergo leukapheresis)

· No known hypersensitivity to APCEDEN® or any of its constituents.

· Three or fewer bone metastases on a bone scan with minimal symptoms.

· No lymph node lesions greater than 3.0 cm at longest diameter.

· Adequate hematological, hepatic and renal function.

· Normal organ function and normal hematological parameters; laboratory parameters should be within normal range, except following laboratory parameters: HEMOGLOBIN ≥ 10 G/DL; GRANULOCYTES ≥ 1,500/µL; LYMPHOCYTES ≥ 1000/µL; PLATELETS ≥ 100,000/µL; SERUM CREATININ ≤ 2.0 MG/DL; SERUM BILIRUBIN ≤ 2.0 MG/DL; AST AND ALT ≤ 2 X THE NORMAL UPPER LIMITS; LDH ≤ 1,5X NORMAL UPPER LIMIT; CRP ≤ 1,5X NORMAL UPPER LIMIT; PROTHROMBIN TIME (PT) INTERNATIONAL NORMALIZED RATIO (INR) AND PARTIAL THROMBOPLASTIN TIME (PTT) WITHIN NORMAL LIMITS

· No brain metastases leptomeningeal involvement (other than astrocytomas)

· No complete tumor obstruction (e.g., bronchus, ureter, or bowel)

· Patient should not be taking concurrent corticosteroids as these may subside the immune function and interfere with immunotherapy response.

· Patient should be able to adhere to the study visit schedule and other protocol requirements

·      Known positive for hepatitis B or C or HIV.

·      Underlying cardiac disease associated with myocardial dysfunction that requires active medical treatment, or unstable angina related to atherosclerotic cardiovascular disease, or under treatment for arterial or venous peripheral vascular disease

·      Diagnosis of any other invasive cancer which is considered to be life-threatening within the next five years, and/or taking anti-cancer therapy for cancer other than lung cancer (such as continuation of hormonal therapy for breast cancer or prostate cancer diagnosed more than five years earlier).

·      Active infection or other active medical condition that could be eminently life-threatening, including active blood clotting or bleeding diathesis.

·      Pregnant or lactating women.

·      Brain, liver, or lung metastases; uncontrolled heart, liver, lung, or renal diseases or other serious illness.

·      Prior splenectomy.

·      History of moderate to severe lower limb lymphedema, or recent signs of deep venous thrombosis (DVT) or thrombo-embolic disease, or impending stroke.

·      History of immunodeficiency or autoimmune disease; positive HIV, HbsAg or anti-HCV.

Known autoimmune disease, immunodeficiency, or disease process that involves the use of immunosuppressive therapy.

|Study site eligibility criteria

·       The site should have at least one dedicated registered medical practitioner preferably an oncologist.

·       The site should have apheresis facility and adequate healthcare professional for administering the drug through infusion.

·      The site should have informed the sponsor (APAC Biotech) and obtain approval from APAC prior to initiating apheresis

|PSUR frequency

·      Every six months for two years

|Frequency for submission of efficacy data

·      Efficacy data of first 50 patients to be submitted (as per the recommendation of CBBTDEC)

|Version history

·      Version 1.1 updated as per the comments issued in the 11th CBBTDEC committee held on 23-June-2017. The version now includes primary efficacy endpoints and defined baseline characteristics and key inclusion criteria for each of the approved indication