Advanced Pancreatic Cancer
Conditions
Brief summary
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
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.
Interventions
BIOLOGICALIMM-101
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.
DRUGGemcitabine
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.
Sponsors
Immodulon Therapeutics Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability. | From time of Informed Consent to 30 days post last dose of study medication | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 and progression free survival |
| Overall Response Rate (ORR). | 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). | 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. |
| Overall 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). | Overall and progression free survival in metastatic patients only |
Countries
Cyprus, Ireland, Italy, Spain, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental Gemcitabine plus IMM-101 | 75 |
| Control Gemcitabine monotherapy | 35 |
| Total | 110 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 |
| Overall Study | Death | 20 | 7 |
| Overall Study | Lack of Efficacy | 25 | 17 |
| Overall Study | Physician Decision | 9 | 6 |
| Overall Study | Withdrawal by Subject | 4 | 2 |
Baseline characteristics
| Characteristic | Experimental | Control | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 47 Participants | 19 Participants | 66 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants | 16 Participants | 44 Participants |
| Age, Continuous | 68 years | 66 years | 67 years |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 74 Participants | 33 Participants | 107 Participants |
| Region of Enrollment Cyprus | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Ireland | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Italy | 14 participants | 9 participants | 23 participants |
| Region of Enrollment Spain | 32 participants | 13 participants | 45 participants |
| Region of Enrollment United Kingdom | 25 participants | 9 participants | 34 participants |
| Sex: Female, Male Female | 37 Participants | 14 Participants | 51 Participants |
| Sex: Female, Male Male | 38 Participants | 21 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 22 / 75 | 7 / 35 |
| other Total, other adverse events | 73 / 75 | 35 / 35 |
| serious Total, serious adverse events | 36 / 75 | 10 / 35 |
Outcome results
Primary
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.
Time frame: From time of Informed Consent to 30 days post last dose of study medication
Population: The safety analysis set included all randomised patients who received at least one dose of the study drug. One patient in the Gemcitabine plus IMM-101 group was withdrawn prior to administration of study treatment due to a worsening of his physical condition.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental | Safety and Tolerability. | With Treatment Emergent Serious Adverse Events (TESAEs) | 38 participants |
| Experimental | Safety and Tolerability. | With Treatment Emergent Serious Adverse Events (TESAEs) related to IMM-101 | 7 participants |
| Experimental | Safety and Tolerability. | Withdrawn due to a TEAE | 4 participants |
| Experimental | Safety and Tolerability. | With TEAEs related to IMM-101 | 43 participants |
| Experimental | Safety and Tolerability. | With Treatment Emergent Adverse Events (TEAEs) | 73 participants |
| Control | Safety and Tolerability. | With TEAEs related to IMM-101 | 0 participants |
| Control | Safety and Tolerability. | With Treatment Emergent Adverse Events (TEAEs) | 35 participants |
| Control | Safety and Tolerability. | With Treatment Emergent Serious Adverse Events (TESAEs) | 10 participants |
| Control | Safety and Tolerability. | Withdrawn due to a TEAE | 0 participants |
| Control | Safety and Tolerability. | With Treatment Emergent Serious Adverse Events (TESAEs) related to IMM-101 | 0 participants |
Secondary
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.
Time frame: 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).
Population: The Intent To Treat analysis set included all randomised patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental | Overall Response Rate (ORR). | Complete Response | 0 participants |
| Experimental | Overall Response Rate (ORR). | Partial Response | 8 participants |
| Control | Overall Response Rate (ORR). | Complete Response | 0 participants |
| Control | Overall Response Rate (ORR). | Partial Response | 1 participants |
Secondary
Overall Survival in Metastatic Patients Only
Overall and progression free survival in metastatic patients only
Time frame: 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).
Population: The subgroup of patients with metastatic disease at baseline was the largest and accounted for 80.0% of patients in the ITT analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental | Overall Survival in Metastatic Patients Only | 7.0 Months |
| Control | Overall Survival in Metastatic Patients Only | 4.4 Months |
Comparison: The difference between the two treatment groups was tested with a two-sided log-rank test and a Cox regression model was used to estimate the hazard ratio (HR) and its 95% CI and associated p-value.p-value: 0.01195% CI: [0.33, 0.87]Log Rank
Secondary
Survival
Overall and progression free survival
Time frame: 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).
Population: The Intent To Treat analysis set included all randomised patients.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Experimental | Survival | Overall Survival | 6.7 Months |
| Experimental | Survival | Progression Free Survival | 4.1 Months |
| Control | Survival | Overall Survival | 5.6 Months |
| Control | Survival | Progression Free Survival | 2.4 Months |