A Trial Comparing Gemcitabine With and Without IMM-101 in Advanced Pancreatic Cancer

Study Overview
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Brief Summary
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To compare, in patients with advanced pancreatic cancer, the effects of IMM-101 in combination with gemcitabine to gemcitabine alone on safety and tolerability (including QoL), clinical signs and symptoms of disease, selected markers of tumour burden and immunological status, and disease outcome.

Detailed Description
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Patients in the IMM 101 treated group received an initial dose of IMM-101 followed by a maximum of 12 cycles of Gemcitabine (plus IMM-101); patients in the control group received Gemcitabine alone. All patients were to receive Gemcitabine once weekly for 3 consecutive weeks out of every 4 weeks. Patients in the IMM 101 treated group were to receive IMM 101 every 2 weeks for the first 3 doses, followed by a 4 week rest, then IMM-101 every 2 weeks for the next 3 doses. After this time, patients received doses every 4 weeks. Gemcitabine treatment began at least 14 days after the first dose of IMM-101 in the IMM 101 treated group. Patients who completed the Main Study and who provided informed consent were eligible to participate in a long term treatment Sub-Study. All patients received IMM-101 in the open-label, single arm, Sub-Study irrespective of whether they had been randomised to Gemcitabine or Gemcitabine plus IMM-101 in the main study.

Official Title
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A Randomised, Open-Label, Proof-of-Concept, Phase II Trial Comparing Gemcitabine With and Without IMM-101 in Advanced Pancreatic Cancer

Conditions
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Advanced Pancreatic Cancer

Intervention / Treatment
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* Biological: IMM-101
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female; aged ≥18 years. Histologically and/or cytologically confirmed inoperable ductal adenocarcinoma of the pancreas, including the mucinous variant. This will include locally advanced and metastatic disease (stage III/IV). Presence of measurable lesions in at least one site which have not been previously irradiated (bone lesions, ascites and pleural effusions are not considered as measurable), described as any of the following: Any primary tumour with at least bi-dimensionally measurable disease. a) Palpable lymph nodes; b) Deep seated lymph nodes. Liver metastases measurable by computerised tomography (CT) scan. Deep seated soft tissue lesions measurable by CT scan. World Health Organization (WHO) performance status of 0-2 Serum creatinine <140 μmol/L White blood cell (WBC) count, including differential counts within the normal range or, if outside the normal range, considered by the Investigator not to be clinically significant. Life expectancy of >3 months from randomisation. Provided written informed consent to participate as shown by a signature and date on the patient's Informed Consent Form Exclusion Criteria: Acinar cell carcinoma, neuroendocrine tumours, lymphomas or squamous cell carcinomas. Severe, active uncontrolled infection requiring systemic antibiotics, antiviral or antifungal treatments. Any previous chemotherapy treatment for pancreatic cancer. Eligible for resection of the pancreatic primary tumour but has either refused the operation or is considered to be medically unfit for the operation. Clinical or CT evidence of central nervous system (CNS) metastases. Any previous or concurrent malignancy, except adequately treated carcinoma in situ of the cervix, basal cell carcinoma of the skin and/or non-melanoma skin cancer, or if previous malignancy was more than 5 years earlier and there were no signs of recurrence. Any previous treatment with IMM-101 or related mycobacterial immunotherapy. Serum albumin < 26 g/L. C-reactive protein (CRP) > 70 mg/L. Radiotherapy in the 6 weeks prior to screening. Depot corticosteroids in the 6 weeks prior to screening. Chronic use of any systemic corticosteroids and/or immunosuppressant drugs within the 2-week period prior to the first administration of study drug. Female patient of child-bearing potential who is not, in the opinion of the Investigator, using an approved method of birth control. Female patient who were pregnant, breast feeding or planning a pregnancy during the course of the study. A pre-treatment serum pregnancy test measuring human chorionic gonadotrophin (hCG) had to be negative. Had been administered any investigational product e.g. drug, vaccine or device, in the 3 months prior to screening. Surgical or medical condition which, in the judgement of the Investigator, might interfere with the activity of IMM-101, or with the performance of this study. Any uncontrolled concomitant disease (e.g. unstable angina pectoris, congestive heart failure, myocardial infarction, arrhythmias, and uncontrolled severe hypertension) which, in the judgement of the Investigator, might interfere with the activity of IMM 101, or with the performance of this study. A history of serious adverse reaction or serious hypersensitivity to any drug. Known to have a history of human immunodeficiency virus (HIV) or syphilis, current symptomatic Hepatitis B or C. Testing is not required in the absence of clinical signs and symptoms suggestive of infection with HIV. Unable or unwilling to comply with the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Gemcitabine chemotherapy<br>Patients in the control arm will receive normal standard of care - up to 12 cycles of Gemcitabine. Dosing of Gemcitabine is as per the normal prescribing information for pancreatic cancer. | Drug: Gemcitabine<br>* Gemcitabine will be administered intravenously at 1000 mg/m2 over 30 minutes once weekly for 3 consecutive weeks out of every 4 weeks. Chemotherapy will be offered until intolerable toxicity or withdrawal from the study up to a maximum of 12 cycles (i.e. approximately 48 weeks). Dosage reduction with each cycle or within each cycle may be applied based upon the grade of Gemcitabine-related toxicity experienced by the patient using centre's standard protocol.<br>* Other names: Gemzar;|
| Experimental: IMM-101 in addition to gemcitabine<br>Patients in the experimental arm will receive IMM-101 in addition to the current standard of care, namely chemotherapy (Gemcitabine). The treatment regimen with IMM-101 will be every 2 weeks for the first 3 doses followed by a rest of 4 weeks then every 2 weeks for the next 3 doses followed by every 4 weeks thereafter. For patients in the active group, chemotherapy (Gemcitabine) will begin at least 14 days after first dose of IMM-101. Chemotherapy plus IMM-101 will be offered until intolerable toxicity or withdrawal from the study up to a maximum of 12 cycles (i.e. approximately 48 weeks). Patients who complete the Main Study and who provide informed consent are eligible to participate in a long term treatment Sub-Study (IMM-101-002A) | Biological: IMM-101<br>* IMM-101 is a suspension of heat-killed whole cell M. obuense in borate-buffered saline. A single 0.1 mL intradermal injection of IMM-101 (10 mg/mL) will be administered every 2 weeks for the first 3 doses followed by a rest of 4 weeks then every 2 weeks for the next 3 doses followed by every 4 weeks thereafter. Chemotherapy plus IMM-101 will be offered until intolerable toxicity or withdrawal from the study up to a maximum of 12 cycles of gemcitabine.<br>* Other names: Heat killed whole cell Mycobacterium obuense (M. obuense);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability. | A clinically relevant deleterious effect of IMM-101 on safety and tolerability profiles was judged by: Local and systemic toxicities. Number, type and degree of toxicities as measured by the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) v4.0. Adverse events were collected from time of Informed Consent to 30 days post last dose of study medication IMM-101 does not appear to confer an incremental safety burden beyond that associated with chemotherapy and the disease itself. No new safety signals were identified from this study. The numbers of SAEs by preferred term were low, such that no trends could be inferred from these data and no significant SAEs attributable to IMM 101 were observed. | From time of Informed Consent to 30 days post last dose of study medication | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | Overall and progression free survival | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year (or longer in the case of patients who entered the long term treatment sub-study, up to 5 years). | 
| Overall Response Rate (ORR). | A clinically relevant improvement Overall Response Rate (ORR). Overall response rate was defined as the percentage of patients with a complete response or partial response as assessed by RECIST v1.1 criteria. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year (or longer in the case of patients who entered the long term treatment sub-study). | 
| Overall Survival in Metastatic Patients Only | Overall and progression free survival in metastatic patients only | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year (or longer in the case of patients who entered the long term treatment sub-study, up to 5 years). |