Pembrolizumab and Olaparib in Recurrent/Metastatic, Platinum Resistant Nasopharyngeal Cancer (POINT)

  • STATUS
    Recruiting
  • End date
    Mar 24, 2028
  • participants needed
    30
  • sponsor
    Gruppo Oncologico del Nord-Ovest
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Updated on 23 April 2022
See if I qualify
cancer
measurable disease
carcinoma
chemotherapy regimen
nasopharyngeal carcinoma
metastatic nasopharyngeal carcinoma

Summary

Recurrence rate after curative treatment for locally advanced Nasopharyngeal carcinoma (NPC) is reported varying from 15% to 30% of cases, while approximately 5-11% of patients present with de novo metastatic disease.

In NPC, the immunogenicity of the cancer cell is derived from accumulated somatic mutations, but also from genomic and proteomic differences between host and Epstein Barr Virus (EBV). However, anti-cancer immune response tends to be feeble. This impaired anti-cancer immunity could be attributed to multiple factors including strategies to escape anti-cancer immunity. One of this is switch to immunosuppressive microenvironment, as well as aberrant negative co-stimulatory signals like PD-L1, that is over expressed in NPC. In 2017, the landmark KEYNOTE-028 trial firstly reported promising antitumor activities and safety profiles of pembrolizumab in previously treated RM-NPC Overall, after the treatment of PD-1 inhibitors, about 25% and 60% of the recurrent or metastatic nasopharyngeal carcinoma patients achieved ORR and DCR, respectively, with a profile of toxicities in line with the use of immune checkpoint inhibitors in other diseases.

Recently, it was found that some non-BRCA-mutated tumors often harbor other alterations in HR genes except for germline BRCA deleterious mutations, thus making these tumors could benefit from PARPi treatment.

PARP could contribute to resistance to chemotherapy induced DNA damage, NPC cell platinum resistant could use PARP to repair and escape apoptosis. In nasopharyngeal carcinoma PARP1 is overexpressed in comparison with normal nasopharyngeal cells, LMP1 (latent membrane protein one) activates PARP1 and increases Poly(ADP-ribos)ylation (PARylation) through PARP1. A preclinical study demonstrates that LMP1+ cells are more sensitive to PARP1 inhibition.

After receiving PARPi treatment, accumulated chromosome rearrangements generate plenty of neoantigens and elevate the immunogenicity of tumor, PARPi-mediated acute inflammation remodels tumor immune microenvironment and drives a systemic Th1-skewing immune response.

Patients in the POINT trial will receive pembrolizumab 200 mg intravenously (IV) on Day 1 of every 3-week dosing cycle (Q3W) and olaparib 300 mg capsules twice a day (BID) every day starting from Day 1 of Cycle 1. Treatment with protocol therapy will continue until objective disease progression, any prohibitive toxicity or until a maximum of 35 treatment cycles (up to 2 years).

Description

Before any study specific procedure is performed the patient will sign an informed consent form.

Every effort should be done to obtain a new tumor biopsy from relapsed-metastatic disease, but a new biopsy is not necessary to participate to the study.

Patients will undergo radiologic staging investigations according to guidelines, including pre-treatment head and neck MRI and whole body FDG-PET (or thorax and abdomen CT scan) and clinical evaluation with fiberendoscopy.

Patients will receive pembrolizumab 200 mg intravenously (IV) on Day 1 of every 3-week dosing cycle (Q3W) and olaparib 300 mg capsules twice a day (BID) every day starting from Day 1 of Cycle 1. Treatment with protocol therapy will continue until objective disease progression, any prohibitive toxicity or until a maximum of 35 treatment cycles (up to 2 years).

Patients who must discontinue one of the two drugs in the combination due to adverse events may continue the study with the other combination drug. Once patients have been discontinued from study treatment, other treatment options will be at the discretion of the investigator.

Dose reductions will be allowed according to protocol-specified rules. Tumor response will be evaluated by clinical/endoscopic evaluation every 3 weeks and by radiological imaging every 9 weeks (±7 days) since treatment start. After the first year, the radiological imaging frequency can be modified as clinically indicated. Radiologic response will be assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1).

Blood samples for plasmatic EBV-DNA analysis will be performed at baseline, and, if positive, at week 3, week 9 and then every 9 weeks since treatment start (however in concomitance with the radiological imagining) and at every follow up visit (in case of EBER-positive tumor).

Patients will be evaluated for treatment safety at each clinical visit by means of clinical and laboratory exams. All adverse events will be recorded by Common Terminology Criteria for Adverse Events (CTCAE), version 5.0; the investigator will assess whether those events are drug related or not. All enrolled patients will be included in overall safety analyses.

Change in the Quality-of-Life (QoL) since baseline using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module (EORTC QLQ-HN43) will be evaluated at first visit, every 9 weeks during treatment and at the follow up visit.

Details
Condition Nasopharyngeal Carcinoma
Treatment Pembrolizumab
Clinical Study IdentifierNCT04825990
SponsorGruppo Oncologico del Nord-Ovest
Last Modified on23 April 2022

Eligibility

 Yes No Not Sure

Inclusion Criteria

Male/female participants who are at least 18 years old
The participant (or legally acceptable representative) provides written informed consent
Histologically confirmed diagnosis of nasopharyngeal carcinoma
Disease not amenable of surgical resection or irradiation with curative intent
Disease progressing within 6 months since previous platinum-based systemic treatment (as concomitant to RT or as first line treatment for RM NPC)
Male participants
A male participant must agree to use contraception as detailed in Appendix 3
of this protocol during the treatment period and for at least 3 months after
the last dose of study treatment and refrain from donating sperm during this
period. Female partners of male patients should also use a highly effective
form of contraception if they are of childbearing potential
Female participants
A female participant must agree to use a contraception as detailed in Appendix
of this protocol during the treatment period and for at least 4 months after
the last dose of study treatment
A female participant is eligible to participate if she is not pregnant (see
Appendix 3), not breastfeeding, and at least one of the following conditions
applies
Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR
A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 4 months after the last dose of study treatment
Measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated
area are considered measurable if progression has been demonstrated in such
lesions
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the start of study treatment
Patients must have a life expectancy ≥ 16 weeks
Adequate organ function as defined in the following table (Table 5.1). Specimens must be collected within 10 days prior to the start of study treatment

Exclusion Criteria

WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137)
Prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to allocation
Note: Participants must have recovered from all AEs due to previous therapies
to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy or alopecia may
be eligible
Note: If participant received major surgery, they must have recovered
adequately from the toxicity and/or complications from the intervention prior
to starting study treatment
Prior radiotherapy within 2 weeks of study intervention start. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease
Received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed
Currently participating in or has participated in a study with an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention
Note: Participants who have entered the follow-up phase of an investigational
study may participate as long as the last dose of the previous investigational
agent was received at least 4 weeks before enrollment
Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years
Note: The time requirement does not apply to participants who underwent
successful definitive resection of basal cell carcinoma of the skin, squamous
cell carcinoma of the skin, superficial bladder cancer, in situ cervical
cancer, or other in situ cancers
Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided those are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention
Severe hypersensitivity (≥Grade 3) to study treatment drugs and/or any of its excipients
Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
History of (non-infectious) pneumonitis that required steroids or has currently pneumonitis
Active infection requiring systemic therapy
Known history of Human Immunodeficiency Virus (HIV) infection. Note: No HIV testing is required unless mandated by local health authority
History of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA qualitative is detected) infection
Note: no testing for Hepatitis B and Hepatitis C is required unless mandated
by local health authority
Known history of active Bacillus Tuberculosis
Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome
Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML
Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting study therapy is 2 weeks
Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting study therapy is 5 weeks for enzalutamide or phenobarbital and 3 weeks for the other agents
History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
Has had an allogenic tissue/solid organ transplant
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