Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001637437
Ethics application status
Approved
Date submitted
16/11/2016
Date registered
25/11/2016
Date last updated
1/02/2022
Date data sharing statement initially provided
1/02/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
Phase I Study of Complete Freund’s Adjuvant (CFA) in Patients with Refractory and Relapsed Solid Tumours
Scientific title
Phase I Study of the safety of Complete Freund’s Adjuvant (CFA) in Patients with Refractory and Relapsed Solid Tumours
Secondary ID [1] 290542 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Solid Tumours 300977 0
Condition category
Condition code
Cancer 300774 300774 0 0
Head and neck
Cancer 300775 300775 0 0
Malignant melanoma
Cancer 300794 300794 0 0
Sarcoma (also see 'Bone') - soft tissue

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In this study, escalating doses of single agent Complete Freund's Adjuvant (CFA) will be administered for the treatment of melanoma, head & neck cancer, sarcoma and renal cancer. Patients will be treated with a combination of intratumoural CFA and intravenous pembrolizumab to characterize the safety and anti-tumour activity of this combination.
CFA will be administered at the start of a 42 day cycle. This cycle will be repeated every 42 days at discretion of the investigator.

One cohort (3 patients) will start at a dose level of 0.5ml of CFA, one will start at 1ml of CFA and the third will start at 2ml of CFA. At any dose level if no dose limiting toxicity (DLT) are observed, the dose will be escalated. Patients must complete 1 cycle of treatment with the minimum safety evaluation and drug exposure, or have had a DLT within the first cycle of treatment to be considered evaluable for dose escalation decisions. CFA dose can be escalated at discretion of the investigator if the patient is deriving benefit and has not experienced DLT or a serious adverse event. Intermediate or additional dose levels of CFA may also be considered depending upon the safety and tolerability of this agent. If a DLT is observed in 1 out of 3 patients at a given dose level, up to an additional 3 patients will be enrolled and treated at that dose level. If patients at that dose level have DLTs, the dose will be decreased to the previous dose level and 3 additional patients will be enrolled at that dose level. When up to 3 additional patients are added to a given dose level, if 1 of the 6 patients has a DLT, that dose will be declared as maximum tolerated dose or recommended phase II dose. If 2 of the first 3 or 2 of the total 6 patients experience DLTs at the initial dose level of 0.5 ml CFA, further enrollment will be halted and the study terminated or amended to evaluate lower doses. Dose escalation will continue until identification of the maximum tolerated dose/recommended phase II dose or a suitable lower dose for expansion.

Pembrolizumab will be administered every three weeks.
Dose will be 2mg/kg.
Intervention code [1] 296399 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 300191 0
To assess the safety and tolerability of CFA in adult subjects with locally advanced or metastatic solid tumors.
Dose will be maintained, reduced or discontinued based on the severity of adverse event and length of time to resolution.
Blood bilirubin grade 2 (>1.5-3.0 x ULN)
AST/ALT elevation grade 3 (>5.0 - 20.0 x ULN) without bilirubin elevation >2.0 x ULN
AST/ALT elevation grade 2 (>3.0 - 5.0 x ULN) AND total bilirubin >2.0 x ULN
ANC <1.0 x 10^9/L without fever and/or platelets <100,000 x 10^9
QTc interval >481 msec
Grade 2 or greater tumour site skin ulceration caused by CFA treatment
Other clinically significant non-hematological AEs related to CFA greater than grade 3
Timepoint [1] 300191 0
Evaluated for toxicity at D1 of each cycle (every 42 days) and upon occurrence of an SAE..
Secondary outcome [1] 329297 0
To assess the antitumour effect of CFA per immune related response to criteria.
Target lesions will be measured at baseline and measured and recorded at each clinic visit. Imaging will be performed every 2 cycles (2x42 days). Response and progression will be evaluated using RECIST 1.1 guideline for immunotherapy.
Timepoint [1] 329297 0
Assessment on day 1 of each cycle (42 days)

Eligibility
Key inclusion criteria
Histologically/cytologically confirmed locally advanced or metastatic solid tumors (melanoma, head & neck, sarcoma, renal and other cancers) for which no curable therapy exists. Melanoma patients will be allowed to enroll in the dose escalation phase of single agent study following progression or intolerance of ipilimumab/pembrolizumab (or both). Patients who are not suitable or decline treatment with ipilimumab/pembrolizumab (or both) will also be allowed to participate during dose escalation. Previous treatment with a PD1 inhibitor agent is not allowed in dose expansion phase. However, previous treatment with ipilimumab is allowed in dose expansion phase.

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.

Adequate marrow function as defined below:
a- absolute neutrophil count greater than or equal to 1.0 x 10^9/L
b- platelets greater than or equal to 100,000 x 10^9/L
c- INR less than 1.5 x ULN

Evidence of at least one measurable and easily accessible cutaneous or subcutaneous lesion that could be injected with CFA but preferably three lesions (other two for a biopsy and tumour assessment each). In patients who have a single measurable lesion, it can be used for intratumoral injection, biopsy and response measurement.

Adequate liver function as evidenced by bilirubin <1.5 times the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <3 times the ULN or <5.0 x ULN if liver metastases are present.

Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A female of childbearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy, or has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

Recovery from all AE of prior cancer therapies including surgery and radiotherapy, to baseline or CTCAE Grade greater than or equal to 1, except for alopecia.

No prior therapy with CFA or similar agents. Melanoma, head & neck cancer, sarcoma and renal cancer patients will be allowed to enrol in the dose escalation phase of the study. However, enrolment into dose expansion phase Ib will be restricted to melanoma patients with no prior exposure to anti-PD1 agent.

Patients with treated brain metastases, provided that they are clinically stable for a period of 30 days prior to study entry.

These criteria will also be in effect for the dose escalation and expansion stages of the study
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Preexisting > grade 2 peripheral neuropathy

Treatment with any of the following anti-cancer therapies prior to the first dose of CFA within the stated timeframes: intravenous chemotherapy within a period of 4 weeks (6 weeks for nitrosourea, mitomycin-C), biological therapy (e.g. antibodies) within a period of time that is ~ 5 t1/2 or less than 4 weeks, whichever is shorter, prior to starting study drug, any other investigational agents within a period of time that is < 5 tl/2 or 4 weeks (whichever is shortest) prior to starting study drug, wide field radiotherapy <4 weeks or limited field radiation for palliation <2 weeks prior to starting study drug.

History of cardiac disease (Congestive heart failure NYHA grade > 2, LVEF < 40% as determined by MUGA scan or ECHO, history of clinically significant ventricular arrhythmias, uncontrolled hypertension, unstable angina pectoris or acute myocardial infarction <6 months prior to starting study drug, QTcF > 450 msec), or history of Torsades de pointes.

Pregnant or nursing (lactating) women.

These criteria will also be in effect for the dose escalation and expansion stages of the study

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Study data will be summarised using descriptive statistics and graphical presentations. The trial does not involve hypothesis testing, so no power calculation will be performed.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
7/10/2016
Date of last participant enrolment
Anticipated
1/10/2023
Actual
Date of last data collection
Anticipated
1/03/2024
Actual
Sample size
Target
26
Accrual to date
9
Final
Recruitment in Australia
Recruitment state(s)
ACT
Recruitment hospital [1] 6934 0
The Canberra Hospital - Garran
Recruitment postcode(s) [1] 14614 0
2605 - Garran

Funding & Sponsors
Funding source category [1] 294970 0
Hospital
Name [1] 294970 0
Canberra Hospital Private Practice Fund
Country [1] 294970 0
Australia
Primary sponsor type
Hospital
Name
Canberra Hospital Medical Oncology Department
Address
Medical Oncology Clinical Trials
Building 19, Level 5
Canberra Hospital
Yamba Drive
Garran, ACT, 2605
Country
Australia
Secondary sponsor category [1] 293790 0
None
Name [1] 293790 0
None
Address [1] 293790 0
None
Country [1] 293790 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296331 0
ACT Health Human Research Ethics Committee
Ethics committee address [1] 296331 0
Research Ethics and Governance Office
Building 10 Level 6
Canberra Hospital
Yamba Drive
Garran, ACT, 2605
Ethics committee country [1] 296331 0
Australia
Date submitted for ethics approval [1] 296331 0
02/09/2015
Approval date [1] 296331 0
05/02/2016
Ethics approval number [1] 296331 0
Eth.11.15.217

Summary
Brief summary
This study will investigate the safety of Complete Freund’s Adjuvant (CFA) in Patients with Refractory and Relapsed Solid Tumours.

Who is it for?
You may be eligible to join this study if you are aged 18 years or above, have a histologically or cytologically confirmed locally advanced or metastatic solid tumor (melanoma, head & neck, sarcoma, renal and other cancers) for which no curable therapy exists.

Study details
This study involves the use of an investigational drug called CFA. "Investigational" means that the drug has not yet been approved by the Therapeutic Goods Administration (TGA) for treatment of cancer. CFA consists of three ingredients: mineral oil, surfactant, and heat-killed mycobacterium. Injection of CFA into tumour creates a localised depot of killed bacteria, which are slowly released over weeks. This causes an influx of immune cells to the site on injection, and initiates a powerful immune response. The other drug (pembrolizumab) is an approved novel agent for the treatment of metastatic melanoma. Participants in the study will receive CFA in combination with pembrolizumab.

CFA will be administered in 42 day cycles starting at a dose of 0.5 ml for the first cohort of three patients. These patients will be monitored closely and provided there are no safety concerns additional patients will be enrolled and treated with 1.0 ml of CFA and subsequently a third cohort will be enrolled with a starting dose of 2.0 ml of CFA. Once a participant experiences an adverse event as a result of the CFA dose, this dose level will be expanded with three additional patients enrolled. If two of the six participants experience a reaction the dose will be decreased to the previous level and three additional patients will be added. If one of the six patients experience a reaction that dose will be declared the maximum tolerated dose for CFA. Pembrolizumab will be administered following approved guidelines (2mg/kg) on day 2 of the first cycle and then every three weeks.

Safety of CFA will be assessed at Day 1 of each 42 day cycle. Participants will be followed for up to 30 days after removal from treatment to determine therapeutic benefit and anti-tumour effect of CFA. Patients removed from treatment for unacceptable adverse events will be followed up until resolution or stabilization of the adverse event.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 70442 0
Prof Desmond Yip
Address 70442 0
Building 19, Level 5
Canberra Hospital
Yamba Drive
Garran, ACT, 2605
Country 70442 0
Australia
Phone 70442 0
+612 6244 2220
Fax 70442 0
Email 70442 0
[email protected]
Contact person for public queries
Name 70443 0
Mrs Olive Doig
Address 70443 0
Building 19, Level 5
Canberra Hospital
Yamba Drive
Garran, ACT, 2605
Country 70443 0
Australia
Phone 70443 0
+612 51243856
Fax 70443 0
Email 70443 0
[email protected]
Contact person for scientific queries
Name 70444 0
Prof Desmond Yip
Address 70444 0
Building 19, Level 5
Canberra Hospital
Yamba Drive
Garran, ACT, 2605
Country 70444 0
Australia
Phone 70444 0
+61 251242220
Fax 70444 0
Email 70444 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Undecided IPD


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
14867Clinical study reportCarroll CSE, Malik L, Elliott KF, Andrew ER, Brennan M, Meyer J, Hintze, Lappin C, MacPherson P, Shulte KM, Dahlstrom JE, Tamhale R, Neeman T, Herbert EW, Orange M, Yip D, Allacvena R, Fahrer A. A simple and effective bacterial based intratumoural cancer immunotherapy. Journal for ImmunoTherapy of Cancer ;9:e002688.https://dx.doi.org/10.1136/jitc-2021-002688[email protected] 371846-(Uploaded-09-10-2021-20-56-04)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseSimple and effective bacterial-based intratumoral cancer immunotherapy.2021https://dx.doi.org/10.1136/jitc-2021-002688
N.B. These documents automatically identified may not have been verified by the study sponsor.