- Trials closed
To assess the safety of continuous IV administration of the CXCR4 antagonist, plerixafor, at potentially active plasma concentrations and assess its impact on the immune microenvironment in patients with advanced pancreatic, high grade serous ovarian and colorectal adenocarcinomas
In the absence of resectability, pancreatic ductal adenocarcinoma (PDAC) is almost uniformly lethal; therefore there is a great need to identify novel therapeutic approaches. Only 10-20% of patients present with operable disease and with addition of adjuvant chemotherapy, 5-yr survival in this group is 29%1-3. At presentation, 50-60% of patients are diagnosed with metastatic disease and following palliative gemcitabine-based chemotherapy, the median survival is 5.7 months4,5 and combination treatment (FOLFIRINOX) is reported to improve median survival to 11 months.
Analysis of the immune microenvironment, in both human and mouse PDAC tumours, demonstrates the exclusion of CD3+ T-cells from the areas containing cancer cells, although T-cells are present in the stromal regions of PDAC. This paucity of T-cells in tumour tissue is likely to contribute to the lack of immune control of PDAC. The CXCL12/CXCR4 signalling axis has been implicated in cancer metastasis, growth and survival. In the genetically engineered KPC mouse model of PDAC, CXCL12, which is produced by FAP+ stromal cells, is abundantly bound to the surface of cancer cells7. Engagement of CXCR4 on T-cells by cancer cell-bound CXCL12 is likely to result in the killing of T-cells, thereby explaining the localized lack of T-cells in the region of tumour cells.
We have shown that, in the KPC model of PDAC, continuous administration of plerixafor for one week 1) rapidly induces the accumulation of T cells amongst cancer cells, 2) halts the growth of the tumour, and 3) greatly diminishes the number of Ki67+ replicating cells and p53+ cancer cells7. We hypothesize that the disruption of the CXCL12/CXCR4 axis in human PDAC (and other tumours, justification below) will permit T-cell infiltration into tumours and enable tumour cell killing, as was observed in the KPC model. Our intent is to demonstrate similar effects in patients with pancreatic (and possibly other) adenocarcinomas.
If successful, this approach will then be expanded, in subsequent protocols, to examine the inhibition of CXCR4, in combination with T-cell activation focussed therapies (such as anti-PD1 and anti-PDL1 antibodies). These agents have demonstrated clinical activity in an increasing number of tumour types. Data in patients with melanoma are particularly compelling, however, in contrast, no responses were seen in 14 patients with PDAC treated with anti-PDL18 or 27 patients treated with anti-CTLA49. As stated above, we hypothesise that this is related to the CXCL12, bound to the surface of the cancer cells, engaging with CXCR4 on T-cells and leading to their death.
This trial is required to establish whether relevant plasma concentrations of plerixafor can be achieved safely in patients with advanced pancreatic, high grade serous ovarian and colorectal cancer. This is a prospective, non-randomised, open-label, Phase I, dose-escalation trial of plerixafor in patients with histological documentation of advanced pancreatic, high grade serous ovarian or colorectal adenocarcinoma. We will investigate the feasibility of administering plerixafor in terms of safety and will try to identify the proof of mechanism in patients. This trial will follow the standard 3+3, Phase I trial design, leading to a treatment expansion phase to confirm the RP2D.
Main inclusion criteria
Patients are eligible for inclusion in the trial if they meet all of the following criteria:
- Aged 16 years or over (In the US, aged 18 years or over only).
- Dose escalation phase only: Patients with inoperable, histologically proven locally advanced or metastatic pancreatic, high grade serous ovarian or colorectal adenocarcinoma, refractory to conventional chemotherapy or a patient who has declined conventional chemotherapy OR;
- Treatment expansion phase only: Patients with inoperable, histologically proven locally advanced or metastatic pancreatic, refractory to conventional chemotherapy or a patient who has declined conventional chemotherapy.
- Tumour lesions considered to be accessible for core biopsy and immunostaining assessment.
- ECOG performance status 0-1.
- Life expectancy of at least 12 weeks.
- All women of child-bearing potential and all sexually active male patients must agree to use effective contraception methods throughout the trial and for 3 months after the final dose of trial drug.
Main exclusion criteria
- Inadequate haematological function defined by:
- Absolute neutrophil count (ANC) <1.5 x 109/L
- Absolute lymphocyte count < normal level for institution
- Haemoglobin <9.0 g/dL (90 g/L) (may be increased to this level with transfusion as long as there is no evidence of active bleeding)
- Platelets <100 x 109/L
- Clotting; INR >1.3
- Inadequate renal function defined by calculated creatinine clearance by Cockcroft-Gault of <50 ml/min.
- Inadequate hepatic function defined by:
- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN) or >5 x in the presence of liver metastases
- Total bilirubin >1.5 x ULN
- Current treatment (within 28 days of entry) with chemotherapy, steroids or other immunosuppressive drugs.
- Significant acute or chronic medical or psychiatric condition, disease or laboratory abnormality which in the judgment of the Investigator would place the patient at undue risk or interfere with the study.
- Cardiac co-morbidity:
- Past history of significant rhythm disturbance (e.g. SVT, AF or ventricular irregularities)
- Requirement for pacemaker.
- Myocardial infarction in the previous 6 months.
- Known medical history of proven postural hypotension.
- Active infection.
- Patients with known allergy to plerixafor or its excipients.
- Patients known to have hepatitis B, hepatitis C or HIV infection.
- Women, who are pregnant, plan to become pregnant or are lactating (during the study or for up to 3 months after the last dose).
Funders and sponsors
Prof Duncan Jodrell
Cancer Theme Email: firstname.lastname@example.org