Table 2.
Definition of dose limiting toxicities in all three study protocols
| NSCLC trial | Breast cancer trial | HNSCC trial | All three trials | |
|---|---|---|---|---|
| Acute toxicity phase |
Non-hematological toxicity: • Radiation pneumonitis gr ≥ 3 • Any other non-hematological gr ≥ 3 toxicity (other than radiation esophagitis/dysphagia, radiation dermatitis, fatigue, nausea and vomiting, weight loss, anorexia and dehydration) • Gr ≥ 4 radiation esophagitis/dysphagia, radiation dermatitis, fatigue, nausea and vomiting, weight loss, anorexia and dehydration in the presence of maximal support/treatment. • Gr 3 radiation dermatitis present ≥ 9 weeks after end of treatment • Gr 2 cardiac or neurological toxicity Treatment discontinuation#: • Any radiotherapy discontinuation • Cisplatin cumulative discontinuation for > 20% of the total prescribed dose |
Non-hematological toxicity: • Radiation dermatitis gr 4 except if this is associated with and at the localization of the ulcerative tumour • Radiation dermatitis gr 3 present ≥ 7 weeks after end of treatment • Pain related to dermatitis gr ≥ 3 present ≥ 7 weeks after end of treatment • Edema breast gr 3 in the presence of maximal support/treatment • Nausea and vomiting gr ≥ 3 in the presence of maximal support/treatment • Esophagitis gr ≥ 3 • Any other non-hematological toxicity gr ≥ 3 (except radiation dermatitis, pain, edema, nausea, vomiting, anorexia, weight loss and fatigue) Treatment discontinuation: • Any radiotherapy discontinuation due to toxicity attributable to radiotherapy, irrespective of the grade of toxicity • Cumulative discontinuation of radiotherapy for > 5 fractions due to toxicity attributable to olaparib, irrespective of the grade of toxicity |
Non-hematological toxicity: • Gr ≥ 4 mucositis, dysphagia, radiation dermatitis, anorexia • Gr ≥ 3 hemorrhage, aspiration, trismus • Gr ≥ 3 radiation dermatitis present ≥ 8 weeks after end of treatment • Gr ≥ 3 nausea and/or vomiting in the presence of maximal support • Only in patients with oropharynx SCC: gr ≥ 3 larynx edema • Weight loss ≥ 20% of baseline weight Treatment discontinuation#: • Cumulative discontinuation of radiotherapy for > 3 fractions |
Hematological toxicity: • Neutropenia gr 4 lasting for > 6 days • Neutropenic fever gr ≥ 3 • Thrombocytopenia gr 3 in the presence of bleeding; Thrombocytopenia gr ≥ 4 • Anemia gr 3 in the presence of blood transfusion dependency as judged by the PI; Anemia gr ≥ 4 Other: • Any other toxicity, which in the judgment of the Investigator is viewed as DLT Treatment discontinuation#: • Olaparib total discontinuation for > 20% of the total prescribed dose |
| Late toxicity phase |
Non-hematological toxicity: • Gr ≥ 3 radiation pneumonitis, brachial plexopathy, esophageal stenosis, esophageal ulcer, esophageal necrosis, esophageal hemorrhage • Gr ≥ 2 myelitis, esophageal perforation, esophageal fistula |
Non-hematological toxicity: • Fibrosis gr ≥ 3 outside the boost field AND if applicable outside the skin bolus field • Skin ulceration gr ≥ 2 except if this is persisting acute toxicity associated with and at the localisation of the ulcerative tumour • Radiation pneumonitis gr ≥ 3 • Esophagitis gr ≥ 3 • Brachial plexopathy gr ≥ 2 except if there was pre-existing brachial plexopathy or if the brachial plexopathy is tumour progression related |
Non-hematological toxicity: • Gr ≥ 4 dysphagia, aspiration • Gr ≥ 3 hemorrhage, skin atrophy, trismus, osteoradionecrosis, radiation dermatitis, pneumonitis • Gr ≥ 2 fistula, myelitis • Gr ≥ 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: gr ≥ 3 larynx stenosis |
Hematological toxicity: • Blood transfusion dependency as judged by the PI, unless the patient has progressive disease • Development of MDS/AML Other: • Any other toxicity, which in the judgment of the Investigator is viewed as DLT |
The acute and late toxicity phases are defined as between start of treatment until three months after end of study treatment, and between three months until one year after end of study treatment respectively. All toxicities are graded according to CTCAE version 4.03 and are only considered a dose limiting toxicity (DLT) if they are assessed by the investigator as possibly, probably or definitely related to the combination of radiotherapy and olaparib. # Treatment discontinuation can be intermittent and/or continuous and is only considered a DLT if this is due to toxicity attributable to the combination study treatment, irrespective of the grade of toxicity. Gr = grade, ADL = activity of daily living, SCC = squamous cell carcinoma, MDS = myelodysplastic syndrome, AML = acute myeloid leukemia