Targeted Therapy of Advanced Biliary Tract Cancers - A Phase 2 Clinical Study

Phase 2

Recruiting

• Conditions: Intrahepatic bile duct carcinoma, (2) ICD-10 Condition: C240||Malignant neoplasm of extrahepaticbile duct, (3) ICD-10 Condition: C23||Malignant neoplasm of gallbladder,

• Registration Number: CTRI/2020/05/025147
• Lead Sponsor: Armed Forces Medical Research Committee

Brief Summary

Brief Summary –

 Advanced biliary tract (Gallbladder & Cholangiocarcinoma) cancers carries dismal prognosis due to lack of prospective research. Gallbladder (GBC) is the third common cancer in females with ASR of 10/100000 population. In India each year >18,000 new gall bladder cancers are diagnosed.More than 80% present in advanced/unresectable stage and median survival of untreated patient is 2-4 months. It is highly aggressive cancer having poor outcomes across the globe. It is the commonest cause of cancer related death in Chile and in northern India (1).  GBC has certain peculiarities like anatomical location which makes the detection of cancer difficult in early stages. It presents with obstructive jaundice which precludes early GBC diagnosis.  Currently, standard of practice for advanced biliary tract cancer is palliative chemotherapy (Gemcitabine + Cisplatin), leading to median overall survival of around 1 year in western literature which predominantly includes cholangiocarcinomas (2,3). Atul Sharma et al first studied the role of chemotherapy versus best supportive care in advanced GBC (4) and established the role of chemotherapy.  Genetically, majority of GBC are carrying p53 mutations which may lead to resistance to chemotherapy. Combination of Gemcitabine and Platinum; Gemcitabine-Cisplatin (Gem-Cis) or modified Gemcitabine-Oxaliplatin (mGemOx) are first line therapy for metastatic/unresectable GBC based on randomized studies (5). Five-year survival rates of gall bladder cancers are 50% for stage I, 28% for stage II, and less than 10% for inoperable stage III cancers. This suggests that even curative surgery is not successful in majority of GBC patients whose tumor has spread beyond muscle layer or has involved lymph nodes. GBC is enriched with Her2neu amplification in 17-20% of cases, Her3neu amplification in 10 % of cases. MET amplifications are seen in around 5% of cases (6,7,8). These targets have been treated successfully in other malignancies and are routinely used in clinical practice.

Departmental study (in press with South Asian Journal of Cancer, PubMed indexed) at Army Hospital Research & Referral, New Delhi, has revealed that GBC has 16% Her2neu amplification, 10% has Her3neu amplification/mutation and 5% has MET amplification. These targets have available therapies like Trastuzumab, Lapatinib and Crizotinib respectively. These targeted therapies have revolutionized treatment in Breast and lung cancers. As Gallbladder cancer is an orphan disease in terms of research due to rarity of this disease in western word, further research is urgently needed for role of targeted therapy in GBC. Similarly, intrahepatic and extrahepatic Cholangiocarcinoma are also less studied. Multiple other genetic alterations are seen in Gallbladder cancer which have targeted therapies available. For example, PIK3CA mutations and FGFR amplification. In our study, PIK3CA mutations were seen in 16% of cases.

Next generation sequencing is the most sensitive test to detect genomic alteration. Foundation Medicine is the US-FDA and DCGA approved test available in India for detection of these genomic alterations. Forty-five percent of advanced GBC cancer had some form of actionality with newer agents. Comprehensive profile also gives understanding of the possible mechanisms of resistance for these therapies. For example, concurrent Her2neu mutation was found in 40% cases which may be resistant to Trastuzumab but may respond to Lapatinib. This study aims at treating these patients with targeted therapy and find out country and disease specific unanswered questions.

If medicines are available through patient/physician access program, patient will also be considered for the same. Targeted therapies will be used as first line therapy along with available standard of care. First line targeted therapy will be preferred over second line use wherever possible. All patients will be followed weekly with CBC, LFT & RFT, and as per tolerance schedule will be adjusted. All patients will be evaluated after three cycles of therapy and six cycles thereafter.

Statistical considerations-Total number of 100 patients will be considered. Out of this, 30% will be having Her2neu and/or Her3neu positive. These patients will be treated with targeted therapies. For alpha level of 0.05 and response rate of 70% (+/-15%), for a phase 2 study, sample size of 35 is considered. Other patients will be considered for targeted therapy.

Targeted therapies will be administered for following Targets as therapy arms.

 Arm A. Trastuzumab plus GemCis/Ox for Her2neu amplification (standard dose Trastuzumab 1st cycle 8mg/kg, followed by 6 mg/kg every 3 weeks)

Arm B. Trastuzumab and Lapatinib plus chemotherapy for Her2neu amplification/mutation (Lapatinib 250 mg 5 tablets OD on empty stomach till

progression).

Arm C. Crizotinib for MET amplification (Tab Crizotinib 250 mg BD till progression)

Arm D. Her3neu mutation/amplification – Trastuzumab and Lapatinib plus chemotherapy for Her2neu amplification/mutation

(Lapatinib 250 mg 5 tablets OD on empty stomach till progression).

Arm E. Everolimus (5 mg BD till progression) plus chemotherapy will be used for PIK3 mutated patients. If available Alpelisib, would be

considered.

  References

 1.        Malhotra RK, Manoharan N, Shukla NK, Rath GK. Gallbladder cancer incidence in Delhi urban: A 25-year trend analysis. Indian J Cancer. 2017 Oct 1;54(4):673.

2.        Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer. N Engl J Med.

2010 Apr 8;362(14):1273–81.

3.        Valle JW, Furuse J, Jitlal M, Beare S, Mizuno N, Wasan H, et al. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials. Ann                 Oncol Off J Eur Soc Med Oncol. 2014 Feb;25(2):391–8.

4.        Sharma A, Dwary AD, Mohanti BK, Deo SV, Pal S, Sreenivas V, et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized             controlled study. J Clin Oncol Off J Am Soc Clin Oncol. 2010 Oct 20;28(30):4581–6.

5.         Sharma A, Shukla NK, Chaudhary SP, Sahoo R, Mohanti B, Deo SVS, et al. Final results of a phase III randomized controlled trial comparing modified gemcitabine +                        oxaliplatin (mGEMOX) to gemcitabine+ cisplatin in management of unresectable gall bladder cancer (GBC). J Clin Oncol. 2016 May 20;34(15\_suppl):4077–4077.

6.         Javle M, Rashid A, Churi C, Kar S, Zuo M, Eterovic AK, et al. Molecular Characterization of Gallbladder Cancer using Somatic Mutation Profiling. Hum Pathol. 2014

Apr;45(4):701–8.

7.         Javle M, Churi C, Kang HC, Shroff R, Janku F, Surapaneni R, et al. HER2/neu-directed therapy for biliary tract cancer. J Hematol OncolJ Hematol Oncol. 2015 May 29;8:58.

8.         Galdy S, Lamarca A, McNamara MG, Hubner RA, Cella CA, Fazio N, et al. HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a

potential therapeutic target? Cancer Metastasis Rev. 2017;36(1):141–57.

Detailed Description

Not available

Study Timeline

• Study Start: 2020-05-15
• Last Update Posted: 2023-07-30

Recruitment & Eligibility

• Status: Open to Recruitment
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

• Histologically proven cases of adenocarcinoma of gallbladder and Cholangiocarcinoma.
• Locally advanced, unresectable or metastatic disease ECOG Performance status <2 Adequate bone marrow function reflected Hemoglobin > 8 gm/dl, TLC > 4,000/cumm (ANC>1,500/cumm), and Platelets >1,00,000/cumm) Serum creatinine <1.8 mg% Serum bilirubin < 3 mg% Liver enzymes (SGOT and SGPT) within 3 times the upper normal limit No prior exposure to gemcitabine, Oxaliplatin, cisplatin, capecitabine or radiation therapy.

Exclusion Criteria

• Women of reproductive age group not practicing contraception.
• Lactating and pregnant women.
• History of previous carcinoma in last 5 yrs.
• Active hepatitis B, C or HIV infection.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Overall response rate,	03 months, 06 months.

Secondary Outcome Measures

Name	Time	Method
Progression free survival,	overall survival

Trial Locations

Locations (5)

ARMY HOSPITAL RESEARCH & REFERRAL, NEW DELHI; 🇮🇳 Delhi, DELHI, India

COMMAND HOSPITAL CC LUCKNOW; 🇮🇳 Lucknow, UTTAR PRADESH, India

COMMAND HOSPITAL EC KOLKATA; 🇮🇳 Kolkata, WEST BENGAL, India

COMMAND HOSPITAL, SC, PUNE; 🇮🇳 Pune, MAHARASHTRA, India

INHS, ASVINI, MUMBAI; 🇮🇳 Mumbai, MAHARASHTRA, India

ARMY HOSPITAL RESEARCH & REFERRAL, NEW DELHI

🇮🇳Delhi, DELHI, India

DR AMOL PATEL

Principal investigator

9999856335

dr.amolpatel@hotmail.com