Study methodology: 

Patients fulfilling the inclusion/exclusion criteria would be assigned to treatment either with Cabazitaxel (Jevtana - dose: 20mg/m² given 3 weekly) or Docetaxel (dose: 75 mg/m² given 3 weekly). Cabazitaxel or Docetaxel will be given to the patients till progressive disease. Patients will be seen weekly till chemotherapy is complete. Efficacy assessment utilizing CT scan will be performed every 6 weeks while the patient is on treatment and every 8 weeks during the follow-up period for patients who have not progressed on study treatment. All recruited patients would be followed up every 3 months for a period of 2 years.

Tissue taken at diagnosis (if specimen available) and tissue at study entry will be taken and stored. This tissue will also be used for exploratory analysis of possible factors /gene mutations related to chemosensitivity/ chemoresistance. DNA / RNA samples from the tumor samples of responders and non responders will be analysed and correlated to the DNA/RNA sequence profile to identify signatures. If possible, biopsy will also be taken after two cycles of chemotherapy. MDR1 expression will be quantified and correlated with response.

Quality of Life (QOL) will be assessed using EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires. The EORTC QLQ-C30 is a 30 item questionnaire composed of multi-item scales that reflects the multidimensionality of the QOL construct. It incorporates five functional scales (physical, role, cognitive emotional and social), three symptom scales – fatigue, pain, nausea and vomiting, global health scale and additional symptoms commonly reported by cancer patients as well as the perceived financial impact of disease and treatment. Score ranges from 0 to 100. A higher score represents a higher level of functioning or a greater degree of symptoms. Similarly, head and neck cancer specific module (EORTC QLQ-H&N35) includes 35 items. Patients have to indicate the extent to which they have experienced the symptoms or problems during the past week. Score ranges from 1 to 4. High score for an item means worse QOL or more problems.

Visit 0 (Baseline) Day -21 to 0

• Written informed consent
• Inclusion/exclusion criteria
• Demographics, physical examination, vital signs, ECOG-PS
• CBC, LFT, Creatinine
• CT-Scan
• QOL scales (EORTC QLQ-C30 and EORTC QLQ-H&N35)
• Assessment of adverse events and concomitant medications
• Biopsy and blood sample for biomarker analysis

Cycle 1

• Day 1: Randomization, study drug administration, assessment of adverse events and concomitant medications
• Day 8 and 15: CBC, assessment of adverse events and concomitant medications

Cycle 2

• Day 1: Physical examination, vital signs, ECOG-PS, CBC, creatinine, LFT, study drug administration, QOL scales (EORTC QLQ-C30 and EORTC QLQ-H&N35), assessment of adverse events and concomitant medications
• Day 8 and 15: CBC, assessment of adverse events and concomitant medications
• Day 21: CT-scan (after every 2 cycles), Biopsy (if possible)

Cycle 3 to N

• Day 1: Physical examination, vital signs, ECOG-PS, CBC, creatinine, LFT, Study drug administration, QOL scales (EORTC QLQ-C30 and EORTC QLQ-STO22), assessment of adverse events and concomitant medications
• Day 8: CBC, assessment of adverse events and concomitant medications

End of Treatment Visit

• Physical examination, vital signs, ECOG-PS, CBC, creatinine, LFT
• Biopsy (DNA/RNA extraction for sequencing)
• QOL scales (EORTC QLQ-C30 and EORTC QLQ-H&N35),
• Assessment of adverse events and concomitant medications

After end of treatment visit (EOT), patients will be followed-up every 3 months for up to 2 years or until death, whichever comes first. During the follow-up visits information on survival and disease progression (if not progressed earlier) will be collected. Ongoing SAE and new or ongoing related AE will be followed-up in follow-up period up to recovery or stabilization.

Safety Assessment

Adverse events will be recorded and graded as per Common Terminology Criteria for Adverse Events (CTC AE Version 4.03) for all patients from the signing of informed consent to the end of the study. In the event of side-effect(s), follow-up would be conducted until the symptoms are resolved. The type and severity of the side-effect, date of onset, date of disappearance, continuation/discontinuation of the protocol therapy, and measures taken (symptomatic treatments), would be recorded on the case record forms as accurately as possible. In addition, causal relationships between a side-effect and the trial drug(s), as well as the rationales for that assessment, would also be recorded as precisely as possible. The causal relationship between an adverse event (side-effect as well as abnormal clinical laboratory finding) and the trial drug(s) would be assessed by the clinician. Investigators are required to assess if there is a reasonable causal relationship with the study drug/treatment regimen administered for each reported AE.  “Reasonable causal relationship” means that, in the Investigators best clinical judgment, there are facts/evidence or arguments to suggest a causal relationship. Possible answers are ‘Yes’ or ‘No’.

Efficacy Assessment

Disease control/clinical benefit rate (CR/PR/SD) would be assessed as per RECIST 1.1 for all randomized patients as per intent-to-treat efficacy analysis. Patients with measurable disease at baseline will only be included in the study. When more than one measurable lesion is present at baseline all lesions up to a maximum of five lesions in total (and a maximum of two lesions per organ) representative of all involved organs will be identified as target lesions and will be recorded and measured at baseline. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. The baseline sum diameters will be used as reference to further characterize any objective tumour regression in the measurable dimension of  the disease. All other lesions (or sites of disease) including pathological lymph nodes will be identified as non-target lesions and will also be recorded at baseline.

Molecular Analysis

Patients resistant to first line chemotherapy will be subjected to a punch biopsy and the tissue retrieved will be cut into smaller pieces and frozen down in liquid nitrogen. Similarly a 5ml sample of the patient’s blood will be collected and subjected to DNA extraction as per standard manufacturer protocols for the same. The DNA sample will be re-suspended in Tris-EDTA (10:1, pH 8.0) and stored at -70⁰ C. At the end of the study, if the patient is found to be resistant to the second-line therapy (either taxotere or cabazitaxel), a second punch biopsy will be conducted and the tissue will be once again cut into smaller pieces and frozen down. On completion of the study, all patient responses to cabazitaxel as a second-line therapy will be compiled and the cohort will be divided into 2 groups of a) Responders and b) Non-responders, as per the criteria of “>50%” reduction in tumor size indicating a “responder” phenotype. Three tissue samples from 3 separate patients from the “responder” group will be subjected to Macromolecule extraction protocols (DNA and RNA extraction) and stored along with the matched DNA sample retrieved from the respective patient’s blood sample. These samples will also be subjected to Immuno Histo-chemical analysis (IHC) to determine tumor fragments having >80% tumor cells and only samples meeting this criterion will be preferentially selected for further molecular analysis. Similarly three tissue samples from 3 separate patients from the “non-responder” group will be subjected to macromolecule extraction protocols and the DNA and RNA obtained will be stored at -70⁰ C along with the matched blood DNA sample. Once again, these samples will be subjected to Immuno Histo-chemical analysis (IHC) to determine tumor fragments having >80% tumor cells and only samples meeting this criterion will be preferentially selected for further molecular analysis. These samples will then be sent to Next Generation Sequencing Facilities (NGS), where they will be appropriately processed for further analysis. New tumors or secondaries that develop in spite of cabazitaxel will also be sampled for NGS studies.

Investigational Treatments

Cabazitaxel 20mg/m² given 3 weekly until progressive disease

Docetaxel: ­­­­­­­­­75 mg/m² given 3 weekly until progressive disease

Pre-medication for Cabazitaxel and Docetaxel is mandatory and will follow the manufacturer’s recommendations (Appendix II and III). All patients will be given primary prophylaxis with G-CSF.