Pembrolizumab and Induction Chemotherapy in Head and Neck Squamous Cell Carcinoma (PICH Study) (PICH)
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|ClinicalTrials.gov Identifier: NCT03114280|
Recruitment Status : Withdrawn (MSD would not able to support the study's continuation after protocol modifications required by ANSM through dose de-escalation of pembrolizumab)
First Posted : April 14, 2017
Last Update Posted : April 8, 2019
Non-randomized phase I/II, open-labeled clinical study, 1-arm, multicenter, of docetaxel (T), cisplatin (P), 5-fluorouracil (F) and pembrolizumab every 21 days for 3 cycles followed by radiotherapy (RT) combined with carboplatin in untreated unresectable locally-advanced Head and Neck Squamous Cell Carcinoma (HNSCC).
The TPF and pembrolizumab combination will be called TP²F.
|Condition or disease||Intervention/treatment||Phase|
|Head and Neck Squamous Cell Carcinoma (HNSCC)||Drug: TPF2 Other: Radiotherapy with carboplatin||Phase 1 Phase 2|
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has been known for decades. Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4, which has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD L2). The structure of murine PD-1 has been resolved. PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail, which is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade. The mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct from, that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells. Expression has also been shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, including non-hematopoietic cells (various tumor cells and stromal cells) as well as hematopoetic myeloid cells (dendritic cells and macrophages…). Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues. Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL). This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an attractive target for therapeutic intervention.
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||0 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||Fluorouracil (F) and pembrolizumab every 21 days followed by radiotherapy (RT) combined with carboplatin in untreated unresectable locally-advanced Head and Neck Squamous Cell Carcinoma (HNSCC).|
|Masking:||None (Open Label)|
|Official Title:||Induction Therapy With Docetaxel, Cisplatin, 5-Fluoro Uracil and Pembrolizumab in Untreated Locally-advanced Unresectable Squamous Cell Head and Neck Carcinoma (Pembrolizumab and Induction Chemotherapy in Head and Neck Squamous Cell Carcinoma. PICH Study)|
|Actual Study Start Date :||March 12, 2019|
|Actual Primary Completion Date :||March 12, 2019|
|Actual Study Completion Date :||March 12, 2019|
docetaxel (T), cisplatin (P), 5 Fluorouracil (F) and pembrolizumab every 21 days followed by radiotherapy (RT) combined with carboplatin
Combination drugs : docetaxel (T), cisplatin (P), 5 Fluorouracil (F) and pembrolizumab every 21 days
Other: Radiotherapy with carboplatin
Radiotherapy (RT) combined with carboplatin
- Phase I : Evaluation of Recommended dose for phase II and characterization of the safety and tolerability profile of pembrolizumab when administered in combination with docetaxel, cisplatin and 5 Fluorouracil [ Time Frame: 12 months post treatment ]To evaluate by using a "3+3 modified schedule" the Recommended Phase 2 Dose (RPD2), Dose Limiting Toxicities (DLT) and Maximal Tolerated Dose (MTD) of the association of pembrolizumab with induction therapy by docetaxel, cisplatin and 5-fluorouracil (TP²F) as first-line treatment for patients with locally-advanced unresectable HNSCC
- Phase II : Progression-free survival [ Time Frame: 12 months post treatment ]Progression-free survival : To evaluate, in terms of progression-free survival rate at 12 months, the efficacy of the association of pembrolizumab with induction therapy by docetaxel, cisplatin and 5-fluorouracil (TP²F) as first-line treatment for patients with locally-advanced unresectable HNSCC ; in order to demonstrate that the addition of pembrolizumab to TPF can increase efficacy without increasing toxicity.
- Phase I : Antitumor activity [ Time Frame: 24 months post treatment ]To document any antitumor activity observed with pembrolizumab in combination with docetaxel, cisplatin and 5 Fluorouracil
- Phase II : Overall survival rate [ Time Frame: 24 months post treatment ]Overall survival rate at 2 years. It will be calculated from the date of study inclusion to the date of the event or to the last known contact of the patient, for those still event free at the time of the last follow-up until 24 months post treatment.
- Phase II : Best Overall response [ Time Frame: 24 months post treatment ]Best overall response rate after induction chemotherapy : Partial Response or Complete Response or Stable Disease after induction chemotherapy (qualitative data)
- Phase II : Best Overall response [ Time Frame: 24 months post treatment ]Best overall response rate after radiation therapy: Partial Response or Complete Response or Stable Disease after radiation therapy (qualitative data)
- Phase II : Objective response rate [ Time Frame: 24 months post treatment ]Objective response rate (ORR) will be determinated by evaluation of Complete Response (CR) and Partial Response (PR)
- Phase II : Progression-free survival (PFS) at 12 months [ Time Frame: 12 months ]Progression-free survival (PFS) is defined by disease recurrence. It will be calculated from the date of study inclusion to the date of the event or to the last known contact of the patient, for those still event free at the time of the last follow-up until 12 months after the treatment.
- Phase II : Level of expression of PD1 before and after treatment [ Time Frame: 7 weeks ]Level of expression of PD1 will be determinated by using quantitative and qualitative data before and after treatment
- Phase II : Evaluation of Safety [ Time Frame: 24 months ]Toxicity will be evaluated according to NCI-CTCAE v4.03
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03114280
|Nice, France, 06000|
|Study Director:||Chrisine LOVERA||Centre Antoine Lacassagne|