Olaparib and Radiotherapy in Head and Neck Cancer
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|ClinicalTrials.gov Identifier: NCT02229656|
Recruitment Status : Recruiting
First Posted : September 1, 2014
Last Update Posted : March 13, 2018
Accelerated, normofractionated radiotherapy is the treatment of choice in stage II-III laryngeal and oropharyngeal squamous cell carcinoma (SCC). However, twenty to thirty percent of patients with stage II-III laryngeal and HPV negative oropharyngeal SCC develop disease progression, mainly due to lack of locoregional control. Radiosensitizers such as cisplatin and cetuximab are added to radiotherapy in more advanced stage of head and neck (H&N) cancer. These radiosensitizers improve loco-regional control and overall survival. Unfortunately, as these radiosensitizers, notably cisplatin, also dose intensify the radiation dose in normal tissues, they also significantly increase toxicity. Adding a more tumor-specific radiosensitizing agent could improve loco-regional control and overall survival without significantly increasing toxicity.
Radiotherapy kills tumor cells by inducing DNA damage. The efficacy of radiotherapy is limited by the ability of tumor cells to repair this DNA damage. Poly(ADP-ribose)polymerase (PARP) is an essential enzyme in base excision repair and single strand break DNA repair, DNA lesions arising from radiation treatment. PARP inhibition and consequently the inhibition of PARP-facilitated DNA repair enhances the anti-tumor activity of radiotherapy, as shown in preclinical studies including head and neck xenograft studies. This radiosensitization is thought to be proliferation dependent and is more pronounced in homologous recombination (HR) deficient cells, providing an opportunity for tumor specific targeting. Genetic analyses suggest that HR deficiency is commonly found in H&N SCC: ATM loss has been reported in 60% of human H&N SCC biopsies and FANC-F defects were reported in 15-21% of human H&N SCC biopsies and cell lines.
The efficacy of radiotherapy is also limited by tumor hypoxia, as tumor hypoxia results in radioresistance. Some PARP inhibiting compounds increase tumor perfusion in xenograft models, thereby reducing hypoxia and specifically sensitizing tumor cells to radiotherapy. Hypoxia is commonly found in H&N SCC and a high pre-treatment hypoxic fraction in H&N SCC tumors is associated with worse outcome. The high prevalence of both hypoxia and HR deficiencies in H&N SCC support the concept of tumor-specific radiosensitization by PARP inhibition in head and neck cancer patients.
Olaparib is a potent PARP inhibitor developed as an anti-cancer drug for HR defected tumors and as a dose intensifier for chemo- and radiotherapy. In humans, olaparib has a low toxicity profile as a single agent, with increasing bone marrow toxicity when combined with chemotherapy. The combination of olaparib and radiotherapy for H&N SCC is expected to improve locoregional control and thereby overall survival. However, this combination treatment has never been tested in humans before. The purpose of this study is to determine the safety and tolerability of radiotherapy for stage II-III laryngeal and stage II-III HPV-negative oropharyngeal SCC with concurrent olaparib.
|Condition or disease||Intervention/treatment||Phase|
|Laryngeal Cancer Stage II Laryngeal Cancer Stage III Carcinoma, Squamous Cell Head and Neck Neoplasms||Radiation: radiotherapy Drug: Olaparib||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||36 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Olaparib Dose Escalation Trial in Patients Treated With Radiotherapy for Stage II-III Laryngeal and Stage II-III HPV-negative Oropharyngeal Squamous Cell Carcinoma|
|Actual Study Start Date :||September 24, 2014|
|Estimated Primary Completion Date :||August 2018|
|Estimated Study Completion Date :||August 2020|
Experimental: radiotherapy and olaparib
Radiotherapy will be given with accelerated fractionation following the DAHANCA schedule Olaparib: dose escalation
Primary tumor and lymph nodes will receive 35 fractions of 2 Gy resulting in a total dose of 70 Gy. Elective fields will receive 35 fractions of 1.55 Gy resulting in a total dose of 54.25 Gy in case a SIB technique is used, or 23 fractions of 2 Gy resulting in a total dose of 46 Gy in case a sequential boost technique is used. The higher total prescribed physical dose to the elective fields in a SIB technique based RT plan compensates for the lower dose per fraction and results in an equal biological effective dose when compared with a sequential boost technique.
The pre-defined dose levels of olaparib are 25mg QD, 25, 50, 100, 200, and 300 mg BID
- The incidence of dose limiting toxicities [ Time Frame: 1 year ]
- Blood transfusion dependency as judged by the PI, unless the patient has progressive disease
- Development of MDS/AML
- Grade ≥ 4 dysphagia
- Grade ≥ 3 hemorrhage, aspiration, skin atrophy, trismus, osteoradionecrosis, radiation dermatitis, pneumonitis
- Grade ≥ 2 fistula, myelitis
- Grade ≥ 2 mucosal ulcer present ≥ 6 months after end of treatment
- Fibrosis limiting joint or orifice movement (e.g. mouth) and/or limiting self care ADL
- Only in patients with oropharynx SCC: grade ≥ 3 larynx stenosis
- Any other (non-)hematological toxicity, which in the judgment of the Investigator is viewed as DLT; excluding fatigue
- acute toxicity [ Time Frame: until 3 months after treatment ]severity, duration and relation with treatment of all adverse events according to CTCAE version 4.03
- late toxicity [ Time Frame: 3 months until 2 year after treatment ]severity, duration and relation with treatment of possibly, probably or definitely related adverse events according to CTCAE version 4.03
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): NCT02229656
|Contact: Marcel Verheij, MD. PhD||+ 31 20 512 firstname.lastname@example.org|
|Contact: Rosemarie de Haan, MD||+31 20 512 email@example.com|
|The Netherlands Cancer Institute||Recruiting|
|Amsterdam, Netherlands, 1066 CX|
|Contact: Marcel Verheij, MD, PhD +31 20 512 2153 firstname.lastname@example.org|
|Contact: Rosemarie de Haan, MD +31 20 512 9085 email@example.com|
|Principal Investigator: Marcel Verheij, MD, PhD|
|Sub-Investigator: Margot Tesselaar, MD, PhD|
|Sub-Investigator: Abrahim Al-Mamgani, MD, PhD|
|Principal Investigator:||Marcel Verheij, MD, PhD||The Netherlands Cancer Institute|