The rationale for the new sequence of pulsed dose chemotherapy proposed in this trial isbased on the hypotheses that current standard dosing of chemotherapy plus pembrolizumabultimately suppresses the immune system and has a negative effect on the efficacy of theanti-PD-1 monoclonal antibody (mAb) therapy and that chemotherapy given after anti-PD-1mAb therapy is associated with higher efficacy.
Chemotherapy plus pembrolizumab plays a significant role in standard of care frontline
treatment in R/M HNSCC and there is a need for improvement in outcomes with this
combination therapy. This trial importantly will test a new dosing and sequence of
pembrolizumab and chemotherapy, with the primary goal of improving efficacy but
secondarily also has the potential to be better tolerated than standard dosing.
Additionally, this trial may have applicability to other solid tumor types where
chemotherapy and anti-PD-1 mAb are currently combined. Based on current data showing that
current repetitive frequent dosing of chemotherapy may lead to immunosuppression and a
detrimental effect on the prolonged duration of response expected from pembrolizumab, and
that chemotherapy efficacy may be higher after anti-PD-1 mAb therapy, this trial will
test a new sequence starting with pembrolizumab with less frequent dosing of chemotherapy
(pulsed dose) to maximize synergy and improve efficacy. Specifically, patients will be
treated with pembrolizumab 200 mg IV q3w with carboplatin/paclitaxel given starting with
cycle 2 of pembrolizumab and continued thereafter every 3rd cycle of pembrolizumab (q9w)
for a total of 4 cycles of carboplatin/paclitaxel. After completion of the 4th cycle of
carboplatin/paclitaxel, pembrolizumab maintenance will be continued at 400 mg IV q6w for
12 cycles for a total of 2 years of therapy. Carboplatin/paclitaxel is being used as the
chemotherapy doublet in this trial because there is more data for immunogenicity and
higher efficacy post anti-PD-1 with taxanes, the potential to be better tolerated than
infusional 5-fluorouracil (5FU), and physician preference for this chemotherapy backbone
including in our Hillman network. Importantly, prior to the immunotherapy era, a phase
III trial compared platinum/taxane to platinum/5FU in R/M HNSCC and found no difference
in efficacy between these regimens, and outcomes in combination with pembrolizumab are
comparable.
Drug: Pembrolizumab
Immunotherapy that works by helping the immune system to kill cancer cells by targeting
and blocking a protein called PD-1 on the surface of certain immune cells called T-cells.
Blocking PD-1 triggers the T-cells to find and kill cancer cells.
Other Name: Keytruda®
Drug: Carboplatin
A chemotherapy drug that contains the metal platinum. It stops or slows the growth of
cancer cells and other rapidly growing cells by damaging their DNA.
Drug: Paclitaxel
A chemotherapeutic agent used as a treatment for various cancers; paclitaxel is a mitotic
inhibitor.
Other Name: Taxol
Inclusion Criteria:
1. Recurrent/metastatic squamous cell carcinoma of the head and neck that is considered
incurable by local therapies.
2. PD-L1 Combined Positive Score (CPS) >1
3. Age > 18 years.
4. Eastern Cooperative Oncology Group (ECOG) Performance Scale (PS) 0-2
5. Measurable disease using Response Evaluation Criteria in Solid Tumors (RECIST) 1
6. Patients must have normal organ and marrow function as defined below:
1. absolute neutrophil count ≥1,000/mcL
2. platelets ≥100,000/mcL
3. total bilirubin ≤ 1.5 X the institutional upper limit of normal (ULN)
4. AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN (≤ 5 X the institutional ULN for
patients with liver metastasis)
5. Creatinine clearance ≥40 mL/min/1.73 m2 for patients with a creatinine levels
above institutional normal.
7. Female subjects of childbearing potential should have a negative urine or serum
pregnancy during the screening period and also prior to receiving the first dose of
study medication. If a urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.
8. Female subjects of childbearing potential should be willing to use one methods of
birth control or abstain from heterosexual activity for the course of the study
through 60 days after the last dose of study medication. Women of childbearing
potential are those who have not been surgically sterilized or have not been free
from menses for > 1 year.
9. Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 60 days after the last dose of study
therapy.
10. Ability to understand and the willingness to sign a written informed consent
document.
11. If known to have prior brain metastases, must not have evidence of active (enlarging
and/or symptomatic lesions) brain disease on MRI/CT evaluation done within 30 days
of consent.
Exclusion Criteria:
1. Patients should not have had prior systemic therapy alone administered in the
recurrent/ or metastatic setting. If a patient received platinum based systemic
therapy which was completed more than 6 months prior to signing consent given as
part of multimodal curative intent treatment for locally advanced HNSCC (This
includes both definitive concurrent chemoradiation and adjuvant chemoradiation) the
patient is still eligible,
2. A patient cannot have received prior anti-PD-1 or anti-PD-L1 monoclonal antibody
(mAb) therapy as systemic therapy for the treatment of recurrent/metastatic disease.
Patients that received anti-PD-1 or anti-PD-L1 mAb therapy as part of multimodality
curative intent treatment of locally advanced disease are still eligible as long as
it has been at least 1 year since prior therapy. Patients that received anti-PD-1 or
anti-PD-L1 mAb therapy as part of radiation for locoregional recurrence will be
eligible as long as it has been 1 year since prior therapy.
3. Squamous cell carcinoma of the skin or of salivary gland origin.
4. Has an active autoimmune disease requiring systemic treatment within the past 3
months, or a syndrome that requires ongoing systemic steroids or immunosuppressive
agents. Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic
therapy or resolved childhood asthma/atopy would be an exception to this rule.
Subjects that require intermittent use of bronchodilators or local steroid
injections would not be excluded from the study. Subjects with hypothyroidism or
Sjogren's syndrome will not be excluded from the study.
5. Has a history of non-infectious pneumonitis that required steroids, evidence of
interstitial lung disease, or currently active non-infectious pneumonitis.
6. Prior malignancy within 2 years that in the investigator's opinion would be likely
to affect the outcomes of the patients R/M HNSCC.
7. Peripheral sensory neuropathy > grade 2 by CTCAE v5.0
8. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
subject's participation for the full duration of the trial, or is not in the best
interest of the subject to participate, in the opinion of the treating investigator.
9. Known allergy or hypersensitivity to carboplatin, other platinum agents,
pembrolizumab, or paclitaxel.
10. Baseline neutrophil count of < 1,500 cells/mm.
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, United States
Investigator: Jennifer Ruth, RN, BSN
Contact: 412-623-8963
ruthj2@upmc.edu
Investigator: Dan P Zandberg, MD
Jennifer Ruth, RN, BSN
412-623-8963
ruthj2@upmc.edu
Dan P Zandberg, MD, Principal Investigator
UPMC Hillman Cancer Center